Immunological modulation of the Th1/Th2 shift by ionizing radiation in tumors (Review)

  • Authors:
    • Jiali Li
    • Zihang Zeng
    • Qiuji Wu
    • Jiarui Chen
    • Xingyu Liu
    • Jianguo Zhang
    • Yuan Luo
    • Wenjie Sun
    • Zhengrong Huang
    • Junhong Zhang
    • Yan Gong
    • Conghua Xie
  • View Affiliations

  • Published online on: June 7, 2021     https://doi.org/10.3892/ijo.2021.5230
  • Article Number: 50
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Abstract

Extensive evidence has documented that the balance between cytokines from T helper type 1 (Th1) and type 2 (Th2) cells is disrupted in the tumorigenic microenvironment compared with immunocompetent individuals. Ionizing radiation (IR) has been reported to markedly modulate the Th1/Th2 polarization in a concentration‑dependent manner. In the present review article, the immune modulation of Th1/Th2 and the IR‑induced crosstalk of the Th1/Th2 shift with immunocytes and tumor cells are summarized. The involvement of the Th1/Th2 shift in post‑radiotherapy complications is highlighted. Specifically, high‑dose IR has been shown to promote the Th2 shift, leading to an immunosuppressive cytokine network, while the impact of low‑dose IR remains controversial. The IR‑induced modulation of the Th1/Th2 shift is mediated by tumor cells and multiple immunocytes, including dendritic cells, tumor‑associated macrophages, cytotoxic T lymphocytes and natural killer cells. However, the excessive production of pro‑inflammatory factors, such as IFN‑γ and IL‑2, by Th1 cells, aggravates the clinical side‑effects of radiotherapy, including radiation‑induced lung and intestinal injury, radiation encephalopathy, as well as other complications. Therefore, further research into the underlying mechanism is required to confirm the potential applicability of the Th1/Th2 shift combined with IR in the treatment of malignant tumors.

1. Introduction

Over the past few decades, there have been significant advances made in immunotherapy for malignant tumors, from adaptive immunocyte modification to novel immune target discovery (1). T helper (Th) cells have been the subject of intensive research on the tumor immune microenvironment (TIME), as they are involved in cellular immunity together with cytotoxic T lymphocytes (CTLs) (2,3). T helper type 1 (Th1) and type 2 (Th2) cells have been found to sustain a functional balance in the normal immune system, while the alterations in cell polarization and cytokine imbalance, referred to as the Th1/Th2 shift, have been associated with numerous immunity-related diseases, as well as malignant tumors (4,5).

Radiotherapy is one of the cornerstones of therapeutic strategies for various tumors. Radiation destroys the double DNA strands of susceptible tumor cells during meiosis, without affecting surrounding tissues to the same extent. It has also been reported that radiation may have a distinct impact on the TIME during the course of prolonged clinical observation (6). Local irradiation markedly alters the immunogenic status of the tumor cells and their ability to elicit an immune response, enhances the initiation of CD8+ T cells and notably augments the secretion of antitumor cytokines (7).

Previous studies (discussed below) have shed light on the impact of the Th1/Th2 shift in the presence of ionizing radiation (IR). Furthermore, the potential role of the Th1/Th2 shift in tumorigenesis and tumor progression has been attracting the attention of researchers. Therefore, the aim of the present review was to summarize the specific implications and effects of radiation on the Th1/Th2 shift in tumor tissues, from molecular mechanisms to clinical impact. The causative association between radiotherapy and immune response was particularly emphasized and highlighted. The outline of this review is presented in Fig. 1.

2. Immunocompetence of Th1/Th2 cells in the Th1/Th2 balance

Th1 and Th2 cells are differentiated from native CD4+ Th0 cells in a cytokine-dependent manner, and represent two different polarization directions, as well as distinct immune response factors in the immunological microenvironment. The main cytokines, decisive transcriptional factors and surface markers of Th1/Th2 cells are summarized in Table I. To maintain immune activation, Th1 cells secrete IFN-γ, IL-2 and TNF-α, inducing adaptive cellular immunity and graft rejection, while Th2 cells produce IL-4, IL-5, IL-6, IL-10 and IL-13, which mainly trigger potent allergic reactions and humoral immunity (8,9). A Th2 shift in the Th1/Th2 balance has been observed during tumor initiation and development (4,10).

Table I

Key molecules in Th1/Th2 cells.

Table I

Key molecules in Th1/Th2 cells.

Cell typeCytokinesDecisive transcriptional factor(Refs.)Surface marker(Refs.)Ligands
IL-12Rβ2(22)IL-12
IL-18R(26)IL-18
Th1 cellsIFN-γT-bet(34)CXCR3(24)CXCL9, CXCL10, CXCL11
IL-2STAT4(34)CCR5(23)CCL3, CCL4, CCL5, CCL3L1
TNF-αLAG-3(21)FGL1, MHC-II
TIM-3(25)Galectin-9
CD30(32)CD30L
IL-1βCCR3(33)CCL5, CCL7, CCL8, CCL11, CCL13,
IL-4GATA-3(36)CCL15, CCL24, CCL26, CCL28
Th2 cellsIL-5STAT6(37)CCR4(27)CCL2, CCL4, CCL5, CCL17, CCL22
IL-6c-Maf(38)CXCR4(30)CXCL12
IL-10CRTh2(28)PGF2α, PGE2, PGI2, thromboxane A2
IL-13ST2L(31)IL-33
IFN-γ Rβ(29)IFN-γ

[i] IL-12Rβ2, interleukin 12 receptor subunit β2; STAT4, signal transducer and activator of transcription 4; LAG-3, lymphocyte activating 3; FGL1, fibrinogen like 1; MHC-II, class II major histocompatibility complex transactivator; TIM-3, T cell immunoglobulin mucin 3; GATA-3, GATA binding protein 3; STAT6, signal transducer and activator of transcription 6; CRTh2, chemoattractant receptor homologous molecule expressed on Th2 cells; PGF2α, prostaglandin F2α; PGE2, prostaglandin E2; PGI2, prostaglandin I2; ST2L, interleukin 1 receptor like 1.

In general, cytokines produced by Th1 cells serve as suppressors against a tumor-promoting microenvironment. Th1-derived IFN-γ induced by IL-12 from antigen-presenting cells has been reported to stimulate the transcription of T-bet in Th1 cells, upregulating IL-12Rβ signals through the JAK/STAT1 pathway, as a positive feedback loop of the IFN-γ cascade (11). IFN-γ has an anti-angiogenic function in the tumor environment, preventing tumor cells from further infiltration and metastasis (12). Low-dose IL-2 binds to the IL-2 immunoreceptor β on the surface of natural killer (NK) cells, thereby enhancing the phosphorylation of STAT3 and STAT5, followed by the overexpression of cyclin B1, leading to selective NK cell proliferation (13). TNF-α, as a multifunctional cytokine, plays crucial roles in inflammation, apoptosis and cell survival. The binding of TNF-α to its receptors triggers cell apoptosis through the caspase cascade, NF-κB activation and receptor-interacting protein recruitment (14). In addition, TNF-α targets the tumor vasculature by destroying the vascular lining and causing hyperpermeability (15). On the other hand, cytokines secreted by Th2 cells are immunosuppressive and promote tumor immune evasion in the TIME. For example, IL-4 combines with IL-4R to form an IL-4/IL-4Rα1 complex, and phosphorylates STAT6, thereby increasing apoptotic resistance and colonization of tumor cells (16). In addition to promoting inflammation, IL-10 has been reported to suppress the expression of major histocompatibility complex (MHC) I and the proliferation of CD8+ T cells, markedly decreasing the cytotoxic effects (17). Notably, IL-10 from tumor cells was observed to abrogate the oncolytic activity of CTLs via activating human leukocyte antigen-G (18).

In addition to differentially secreted humoral factors derived from Th1/Th2 cell populations, both subtypes have been found to be characterized by specific surface protein markers throughout molecular experiments (19,20). IL-18R, IL-12Rβ2, C-C motif chemokine receptor (CCR)5 and C-X-C motif chemokine receptor (CXCR)3, along with lymphocyte activation gene-3, T-cell immunoglobulin and mucin-domain containing-3, have been documented to be highly expressed on Th1 cells (20-26). The Th2 cell population has specific identifiers, such as CD30, CCR3, CCR4, CXCR4, prostaglandin D2 receptor 2, IFN-γRβ and IL-1 receptor-like 1 (19,27-33). Moreover, a Th1/Th2 immune shift occurs accordingly under the influence of different transcriptional factors. T-box transcription factor 21 and STAT4 induce a type 1 shift, while c-Maf and GATA binding protein-3 (GATA-3) induce a type 2 functional cascade (34-38). Due to the lack of affirmatory surface identifiers, Th1/Th2 groups are still defined predominantly based on the representative cytokines they produce.

Depending on the inhibitory roles of the various cytokines, the Th2 shift in the TIME favors a tumor-supporting environment, resulting in tumor immunological resistance.

3. Modulation of the Th1/Th2 imbalance by IR

In addition to the direct damage of DNA double strands and the induction of reactive oxygen species in tumor cells, IR also modulates the molecular balance from immunocytes in the TIME, rendering tumor cells more susceptible or tolerant to IR. Accumulating evidence has uncovered the role of the Th1/Th2 shift induced by IR in the TIME, which consists of tumor cells and immunocytes, including NK cells, macrophages, CTLs and dendritic cells (DCs). The impact of IR on the Th1/Th2 imbalance and its ability to interact with tumor-associated immunocytes, achieving an improved antitumoral immune response to radiotherapy, are reviewed below.

Direct impact of IR on the Th1/Th2 shift

Various doses of IR mediate a distinct Th1/Th2 cytokine imbalance. High-dose IR (HDIR, ≥2 Gy) induces a Th2 shift (Table II) (39-56). Irradiation at 5 Gy notably promotes the secretion of Th2 cytokines, including IL-4, IL-5 and IL-10, most likely through the upregulation of the transcription factor, GATA-3 and c-Maf. The mRNA and protein levels of Th1-secreted molecules, such as IFN-γ and IL-12, are inhibited by the suppression of the STAT signaling pathway in murine splenocytes (39). Similar effects of the Th2 shift were previously observed in tumor-bearing mice with HDIR at 10 Gy. Tumor growth delay was significantly extended after IL-10 suppression in a manner similar to the function of nitric oxide synthase (NOS) inhibitors, leading to immune-enhanced Th1 polarization (40). Furthermore, the exposure of the human immune system to natural HDIR favors a shift to a type 2 response (41,42), with an evidently higher Th2 cytokine production and lower serum antioxidant levels, confirming the IR-induced Th2 shift. On the other hand, potent radioprotectors have been found to reverse the Th2 cytokine shift by IR. Specifically, a combination comprising 3,3′-diselenodipropionic acid, semiquinone glucoside derivative, G-003M, Ginsan polysaccharide, N-acetyl tryptophan glucoside and Fms-like tyrosine kinase 3 ligand, was confirmed to prevent Th1/Th2 imbalance in the TIME, mainly through oxidative stress alleviation and reduction of inflammatory cell infiltration (43-48). Previous results indicated a shift towards Th2 in the TIME mediated by HDIR (39-47,50); however, molecular experiments are required to elucidate the underlying mechanisms.

Table II

Direct impact of IR on the Th1/Th2 shift.

Table II

Direct impact of IR on the Th1/Th2 shift.

Dose typeRadiation doseIrradiation speedCancer cell typeAnimal model/cell typeResponseRemarks(Refs.)
HDIR5 Gy gamma-rays1.394 Gy/minSplenocytesBalb/c miceTh2 shift/(39)
10 Gy X rays2.53 Gy/minSquamous cell carcinomaC3H/HenTh2 shift/(40)
13-fold higher than normalNatural exposurePeripheral blood mononuclear cellsHumanTh2 shiftRadium 22.6 and radon gas(41)
4.5 Gy gamma-rays97.1 cGy/minSplenocytesBalb/c and C57BL/6 miceTh2 shift/(43)
5 Gy gamma-rays0.52 Gy/minSplenocytesSwiss albino miceTh2 shift/(44)
6 Gy gamma-raysNot providedSplenocytesC57BL/6 miceTh2 shift/(45)
7-12 Gy gamma-rays1.2 Gy/minSplenocytesC57BL/6 miceTh2 shift/(46)
20 Gy gamma-rays1.12 kGy/hMacrophage J774AMacrophage J774ATh2 shift/(47)
9 Gy gamma-rays1.038 Gy/minMacrophageC57/Bl6 miceTh1 shift/(48)
2.0 Gy X-rays343 mGy/minSplenocytesICR miceTh2 shift/(50)
2 Gy gamma-rays0.0345 Gy/minSplenocytesC57BL/6 miceTh1/Th2 both elevated/(53)
LDIR0.075 Gy X-rays0.0125 Gy/minSplenocytesKunming miceTh1 shift/(49)
0.075 Gy of X-rays12.5 mGy/minSplenocytesICR miceTh1 shift/(50)
less than 50 millisievert per yearOccupational exposurePeripheral blood mononuclear cellsHuman (radiology staff)Th1 shift/(51)
10 or 50 mGy gamma-rays10 mGy/h~ 204 mGy/minSplenocytes (CD4þ cells)C57BL/6NTh1/Th2 both elevated/(52)
0.01-0.5 Gy gamma-rays0.0345 Gy/minSplenocytesC57BL/6 miceTh1/Th2 both suppressed/(53)
0.4-0.8 Gy gamma-rays0.713 rad/secEhrlich Ascites carcinomaBALB/C miceTh1 shiftWith 0.8 Gy IR induced better Th1 polarization(54)
0.2-1Gy gamma-rays3.93 cGy/minSplenocytes and thymocytesBalb/c miceResults vary with radiation time and organSpleen: Downregulation of Th1 on day 2, upregulation of Th1/Th2 on day 7, no changes on day 14(56)
LDIR Dose gradient0.2, 5, 10, and 20 Gy gamma-raysNot providedSplenocytesC57BI/6jResults vary with IR agents and IR dose0.2, 5,10 Gy: Th1 bias; 20 Gy Th2 bias(55)

[i] IR, ionizing radiation; HDIR, high dose ionizing radiation; LDIR, low dose ionizing radiation.

The Th1/Th2 shift is induced by IR in a dose-dependent manner (Table II) (39-56). Low-dose IR (LDIR, 0.075-0.2 Gy) exerts controversial effects on the cytokine expression profile of unfractionated splenocytes in vivo. For example, LDIR at a dose rate of 12.5 mGy/min was previously reported to increase STAT4 phosphorylation and promote the secretion of the Th1 cytokines, IFN-γ and IL-2, whereas it decreased IL-4 IL-10, IL-21 and TGF-β levels by downregulating GATA-3 (49,50). Similarly, a clinical investigation enrolling laboratory workers and normal radiology staff receiving less than a legal 50 mSv reported a Th1 shift following LDIR, with higher lymphocyte proliferation and IFN-γ production (51). However, LDIR at 50 mGy was reported to promote antitumor immune response by elevating the mRNA levels of both Th1 (IFN-γ) and Th2 (IL-4 and IL-5) cytokines in CD4+ T cells, diminishing TGF-β and regulating mitochondrial ATP synthase (52). Another experimental study revealed that the expression of both Th1 and Th2 cytokines decreased in the presence of LDIR at 0.01, 0.05, 0.1 and 0.5 Gy (53). However, further evidence revealed that LDIR actually affected Th1/Th2 shift in a dose- and time-dependent manner (54-56). For example, in another study, LDIR at 0.8 Gy caused a more prominent Th1 polarization than 0.4 Gy in mice with transplanted Ehrlich ascites carcinoma, while both doses mediated a comparatively significant cancer regression (54). In a similar manner, low-dose gamma-rays were observed to stimulate Th1-type immune responses on day 0, which was terminated by the overexpression tendency of IL-10, resulting in a classical Th2 immunosuppressive status on day 7 (55).

Taken together, these findings indicate that HDIR leads to an immunosuppressive Th2 shift response, while LDIR affects the Th1/Th2 balance with no certain defined effect in a dose- and time-dependent manner. Optimizing the dose and duration of radiotherapy may inhibit immunosuppressive Th2 response and promote a Th1 shift. Identification of potential translational radioprotectors may effectively reverse the Th2 shift of HDIR in the clinical setting. Overcoming these obstacles will help to overcome the limitations of radiotherapy.

Interaction of Th1/Th2 cytokines with other cells in the presence of IR

In the presence of IR, tumor cells as well as multiple immunocytes, including DCs, macrophages, CTLs and NK cells, were reported to partially contribute to the modification of Th1/Th2 shift (Fig. 2).

Figure 2

Indirect impact of IR on Th1/Th2 polarization through crosstalk with other immunocytes and tumor cells in the local tumor microenvironment. IR affects immunocytes heterogeneously at different doses, contributing to the Th1/Th2 shift in the TIME. LDIR promotes the differentiation of classically activated macrophages (M1). M1-derived IL-12 boosts IFN-γ production by Th1 cells. On the contrary, HDIR activates M2 macrophages to increase the production of the M2-derived IL-10, promoting Th2 shift in the tumor microenvironment. LDIR promotes DC proliferation and induces MHC II, IL-2 and IFN-γ through the ATM/NF-κB pathway, while HDIR downregulates IL-12. In addition, LDIR enhances NK cell toxicity via upregulating the secretion of IFN-γ and TNF-α, leading to Th1 polarization. Th2 cytokines, including Il-4, IL-6 and IL-10, favor the creation of an immunosuppressive microenvironment. However, IR partly reverses the Th2 shift in the tumor microenvironment. IR activates NF-κB in tumor cells, mediating TNF-α autocrine signaling to delay tumor growth. Similarly, tumor-derived chemokine CXCL16, induced by IR, recruits CTLs to the TIME. KPNA2 produced by tumor cells induces Th1 differentiation through cytokines in the presence of radiation, mediating antitumoral immunity. TIME, tumor immune microenvironment; Th1, T helper type 1 cell; Th2, T helper type 2 cells; IR, ionizing radiation; HDIR, high-dose IR; LDIR, low-dose IR; DC, dendritic cell; KPNA2, karyopherin α2; CTL, cytotoxic T lymphocyte; NK cell, natural killer cell; CXCL16, C-X-C motif chemokine ligand 16; MHC, major histocompatibility complex; ATM, Ataxia Telangiectasia Mutated.

DCs. As the most efficacious antigen-presenting cells, mature DCs specifically activate CD8+ T cells in antitumor cellular immune response, linking innate with acquired immunity (57). Similar to the Th1/Th2 differentiation, DCs may differentiate into categories based on different factors in the environment. Type 1 DCs (DC1) induce Th1 shift via secreting IL-12 to activate CD40L, while type 2 DCs (DC2) promote IL-4 production by CD4+ Th0 cells, thus causing a Th2 shift (58,59). Indeed, IR may affect the association between DCs and Th1/Th2 cells in a dose-dependent manner. HDIR (2-30 Gy) suppressed IL-12 production while it maintained IL-10 release by mature DCs (60). Of note, it has been reported that this shift of IL-12/IL-10 secretion by activated DCs after IR may promote Th2 shift in the TIME and compromise the curative effects of antitumor therapy (61,62). In a similar manner, IR (6 Gy γ-irradiation) has been reported to mediate a visible reduction in the number of CD8+ DCs in mice, indicating the involvement of DCs in Th2 shift (45), since CD8+ DCs mainly induce Th1 immunity (63,64). On the contrary, LDIR (≤0.2 Gy) was shown to trigger the secretion of IL-2 and IFN-γ by DCs through the Ataxia Telangiectasia Mutated (ATM)/NF-κB signaling pathway (65,66). In summary, clinical radiotherapy may benefit from DC-modulated Th1/Th2 shift at the optimal IR dose.

Macrophages

Macrophage plasticity has been attracting increasing attention due to the polarized activation and differentiation in divergent environments (67). Classically activated M1-like macrophages (IL-12high, IL-10low) primed by Th1-secreted factors (IFN-γ, granulocyte/macrophage-colony-stimulating factor) exert antitumor effects and suppress tumor progression (68). On the other hand, tumor-associated macrophages (TAMs) are characterized by an M2 phenotype (IL-10high, IL-12low) promoted by Th2-secreted cytokines (IL-4 and IL-13) and have been found to be associated with a poor prognosis in cancer (69,70). LDIR facilitates the polarization of TAMs towards the M1 phenotype, potentially suppressing angiogenic responses in endothelial NOS-positive endothelial cells, due to the presence of Th1 cytokines and downregulation of hypoxia-inducible factor-1 (71). Furthermore, very low-dose IR has been shown to upregulate the expression of a whole set of biological functional genes associated with macrophage activation and Th1 immunity in patients with follicular lymphoma (72). However, HDIR has been reported to deteriorate avascular hypoxia, substantially favoring polarization towards the M2 phenotype (73,74), reducing radiosensitivity through heparin-binding epidermal growth factor and accelerated neovasculogenesis, thereby leading to tumor relapse (75). Notably, HDIR has been shown to induce IL-10 oversecretion by M2 macrophages, which is reversed into Th1 immune polarization by NOS inhibitor administration, indicating the participation of M2 macrophages in the Th2 shift (40). A similar activated Th1-type cytokine shift has been observed following irradiation with 20 Gy via inhibition of the NK-1 receptors expressed on the surface of macrophages (47). Hence, promoting IR-induced M1 polarization likely improves the efficacy of radiotherapy and restores the Th1/Th2 balance.

CTLs

CTLs eliminate tumor cells through both secretory (perforin, lymphotoxin, granzyme and TNF-related protein) and non-secretory (Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand) mechanisms (76,77). In a previous study, the curative effects of IR on tumor-bearing mice were eliminated by anti-CD8 monoclonal antibody treatment, confirming the dominant antitumor role of CTLs (78). In another study, in a B16-F0 tumor model, IR (15 or 5×3 Gy) was reported to boost the numbers of tumor-specific CTLs that secrete IFN-γ at the tumor site (79). Of note, the combination of local irradiation and Th1 cell therapy (CpG or recombinant IL-12 or anti-IL-4 antibody), which promote the Th1-type microenvironment, induced the proliferation of tumor-specific CTLs and tumor regression (80-83). Therefore, further investigation of the molecular interactions between CTLs and Th1 cells during radiotherapy will expand the current knowledge on antitumor cellular immunity and promote the application of this combination therapy in the clinical setting.

NK cells

NK cells recognize and kill tumor cells through the activating and inhibitory receptors on their surface (84,85). It was previously reported that the numbers of DX5+IFN-γ+ NK cells significantly decreased, while the numbers of DX5+IL-10+ and DX5+IL-4+ NK cells markedly increased during tumor progression, partly confirming the Th2 shift in the TIME (86). NK cells respond with various functional alterations after being exposed to IR at various doses. LDIR (75-150 mGy) has been shown to increase the proliferation and the levels of cytotoxic effectors of NK cells, including IFN-γ and TNF-α, possibly through the p38/MAPK signaling pathway (87). LDIR stimulates the cytolytic function of NK cells in vivo, leading to the suppression of tumor metastases in animal models (53,88). In a similar manner, the LDIR-induced activation of NK cells has been found to be involved in the antitumor effect of total body irradiation (TBI) (89). On the other hand, the depletion of NK cells following HDIR (5 Gy) with TBI has been shown to lead to a decrease in the levels of Th1-type cytokines in mice, while the injection of NK cells in TBI mice was shown to normalize the IFN-γ levels (90), indicating the contribution of NK cells to the Th1 shift. In addition, NK cells display morphological changes and functional impairment following HDIR (30 Gy), although they retained their ability to bind to targets on tumor cells. However, IL-2 pre-treatment has been shown to maintain the cytotoxic function of NK cells (53,91,92), which is likely associated with NF-κB activation triggered by IL-2/IL-2 receptor binding (93). Collectively, the impact of IR on NK cells varies widely according to the radiation dose, promoting cytolytic function at low doses and abating IFN-γ secretion at high doses. Therefore, the combination of optimal clinical irradiation dose together with IL-2, which preserves NK cell activity, may promote Th1 immunity and maintain the antitumor function of NK cells.

Tumor cells

IR destroys tumor cells via both directly breaking DNA strands and activating tumor-suppressor genes, as well as programming the TIME (94,95). It has been reported that tumor-derived TNF-α in the presence of IR induces the restoration of p53 targets and a rapid re-activation of p65/p50 NF-κB complexes in an autocrine manner (72,96), thus triggering tumor cell death. Furthermore, human breast cancer cells exposed to IR have been shown to produce CXC ligand 16 to recruit CD8+CXCR6+ T cells to the tumor site (97). Similarly, IR-enhanced karyopherin α2 release by colorectal cancer cells increased the expression of TNF-α and IL-12 in DCs, promoting Th1/Th17 differentiation (98,99). On the other hand, tumor cells modify the TIME to create favorable, tumor-promoting conditions. For example, glioma cells secrete Th2 cytokines, including IL-6 and IL-10, to abrogate cytotoxic antitumor immune responses (100). Similarly, IL-4 receptor expression has been shown to increase to accommodate enhanced IL-4 in the TIME of glioblastomas (101). In addition, IR has been shown to upregulate indoleamine 2,3 dioxygenase 1 in colorectal cancer, which blocks the Th1 shift in the TIME and leads to radioresistance (102). Combined with TIME modification agents, IR enables the optimization of immune-mediated tumor destruction and minimizes radiotolerance through promoting a Th1 shift.

4. Clinical side-effects after IR administration caused by the Th1/Th2 shift

A considerable number of studies have revealed that the Th1/Th2 shift is involved in the clinical and biological damage of different organs and tissues in patients following radiotherapy, including radiation-induced lung injury (RLI), radiation-induced intestinal injury (RIII), radiation encephalopathy (RE), as well as other severe complications.

RLI

Numerous studies have highlighted the differential roles of Th1- and Th2-type cytokines in RLI, which include radiation pneumonitis (RP) and radiation fibrosis (RF), occurring within and beyond 3 months following radiotherapy, respectively (103,104). The balance of Th1/Th2 is confirmed to determine the direction and outcome of lung inflammation following lung irradiation (105-116). RP is closely associated with Th1 shift, while RF is more likely associated with Th2 shift.

A number of pro-inflammatory Th2 cytokines, including IL-4, IL-6 and TGF-β, have been reported to be positively associated with RP (105-107). For example, TGF-β, a known key factor involved in inflammation and fibrosis, was found to be markedly upregulated in mice with RP (15 Gy, single dose) via the TGF-β-Smad2/3 pathway (106). In addition, IL-4 was substantially increased in the lungs of irradiated rats within 3 weeks following the administration of a single dose of 20 Gy, at both the transcriptional and translational levels (108). Furthermore, Th2 cytokines, including IL-4, IL-6 and IL-10, have been found to be independent predictive factors for the incidence of RP (all P<0.05) by prospective clinical studies in patients with lung cancer (107,109,110). As regards RF, which is a long-term radiation-induced complication, IL-4 has been reported to play a key role through enhancing collagen synthesis by fibroblasts and inducing the production of TGF-β, leading to irreversible lung injury (111). Furthermore, IL-4 enhances and maintains macrophage activation to promote RF (112). In a similar manner, thoracic HDIR at 12 Gy has been shown to promote the secretion of IL-13 and Arginase-1 through GATA-3 upregulation in vivo, supporting the causative role of Th2 cytokines in pulmonary fibrosis (113). On the other hand, Th1 factors exert a protective function against RF. For example, obvious RF has been observed in IFN-γ-/- mice following whole-thorax irradiation with 18 Gy compared with C57BL/6J (IFN-γ+/+) mice (114). Additionally, the upregulated IFN-γ and downregulated IL-4 levels have been shown to contribute to a deceleration of the fibrotic process when the Th2 shift was partially reversed by TGF-β3 in RF (115). As regards RP, increased IFN-γ levels at 2-3 months following thoracic irradiation have been observed in RP rats of different strains, indicating the role of Th1 cytokines (116). Further investigations of the TGF/Smad pathway identified preclinical RLI protectors, such as CpG-oligodeoxynucleotides and grape seed pro-anthocyanidins (117-119), successfully modifying the Th1-dominant microenvironment to alleviate RLI. In addition, the Th17 cell subpopulation was found to accelerate post-irradiation inflammation and fibrosis in the lung (120,121). Both RF and overt neutrophil infiltration have been shown to be averted following the downregulation of the IL6/TGF-β/IL-17 pathway in irradiated IL17-/- mice (114,122).

Thus, IFN-γ has been confirmed to suppress radiation-induced fibrosis while enhancing the inflammatory response, and Th2 cytokines act as both pro-inflammatory and pro-fibrosis factors during irradiation. Further studies are required to elucidate the interaction between the novel Th17 subpopulation and the Th1/Th2 shift in RLI. A promising preventive strategy for RLI may be reversing the Th2 shift with potential transformable radiation protectors.

RIII

RIII often arises as a complication of radiotherapy in patients with pelvic, abdominal, or retroperitoneal tumors and is attributed to the injury of radiation-sensitive stem cells in the intestinal epithelium (123). It is currently considered that each individual cytokine, rather than a class of cytokines, plays a specific role in RIII. Th1/Th2 factors may be basically divided into two categories, namely the pro-RIII type cytokines, including TNF-α, IFN-γ, IL-1β and IL-6, and the anti-RIII cytokine, IL-10. For example, a TBI trial performed on rhesus macaque monkeys demonstrated that the TNF-α cascade and the upregulation of matrix-dissociated genes were associated with severe intestinal inflammation and mucosal barrier disruption (124,125). These pathological changes may be normalized by granulocyte colony-stimulating factor (126,127). Furthermore, the findings from a novel brachytherapy mouse model revealed a marked increase in IL-1β and IL-6 levels, as high as 100- to 300-fold, following irradiation with 5.5-8 Gy (128), and both cytokines were of notable predictive value for radiation-induced proctitis based on receiver operating characteristic curve analysis (128). The suppression of NF-κB with specific radioprotectors, targeting either the peroxisome proliferator activated receptor-γ/NF-κB or the Toll-like receptor 4/MYD88 innate immune signal transduction adaptor/NF-κB axes, has been shown to contribute to a decrease in the levels of the pro-inflammatory cytokines, IL-6 and TNF-α, in RIII (129-131), which has also been shown to be attenuated through the PI3K/AKT/mTOR pathway (132). In the clinical setting, mesenchymal stem cell (MSC) transplantation has been reported to alleviate RIII by increasing IL-10 and reducing TNF-α and IFN-γ levels in serum (133-136). However, another study stated that the predominant Th17 rather than the Th1/Th2 population was inhibited by adipose-derived MSCs in RIII (137). Therefore, Th1 (TNF-α and IFN-γ) and Th2 (IL-1β, IL-6, IL-10) cytokines play key roles in RIII and may serve as reliable RIII predictors. Further research on Th17 cells may shed more light on the mechanism underlying the development of RIII.

Radiation encephalopathy (RE)

RE is a complication of radiotherapy for craniofacial tumors, and often presents as a series of pathological and morphological alterations of brain structure. Microglial activation has been considered as a potential contributor to inflammatory responses in RE (138). Previous studies have revealed that the induction of the NF-κB and MEK/ERK1/2 signaling pathways may trigger microglial activation after cranial radiation therapy, leading to an increase in the levels of inflammatory factors, such as IL-1β, TNF-α and IL-6 in microglia (139-141). In addition, the abnormal elevation of TNF-α has been found to coincide with the occurrence of neurological abnormalities at 2-3 and 6 months following irradiation in vivo (142). On the contrary, the inhibition of TNF-α and IFN-γ has been shown to prevent severe neurological damage in rats by suppressing hippocampal neuronal apoptosis (143). The observation that patients suffering from less prominent cognitive function impairment after cranial radiotherapy exhibit higher levels of anti-inflammatory IL-10 in serum (144) has suggested the potential use of cytokines against RE. Thus, further preclinical studies are required to investigate the alleviation of microglial activity as well as the promotion of Th2 polarization in vivo.

Other radiation-induced clinical symptoms

Cutaneous radiation syndrome (CRS), which is characterized by extensive inflammatory response, fibrosis or, ultimately, necrosis of the skin, mostly occurs as a consequence of HDIR. The TGF-β/Smad3 pathway mediates inflammation in CRS (145,146). IFN-γ therapy has been observed to ameliorate cutaneous fibrosis, most likely through TGF-β inhibition (147). A clinical randomized trial confirmed that low-dose IFN-γ administration induced a significant reduction in fibrosis in patients with IR overexposure (148). Furthermore, blood-based single-nucleotide polymorphism (SNP) analysis revealed a possible association between SNPs in the IFN-γ gene (rs2069705) and acute radiation-induced skin reactions in patients with breast cancer undergoing adjuvant radiotherapy (149).

TNF-α has been found to be implicated as a potential contributor and underlying target in radiation-induced salivary dysfunction and oral mucositis, as it increased nitric oxide levels in salivary gland epithelial cells and disrupted salivary gland function (150-152). In addition, in radiation-induced esophagitis, manganese superoxide dismutase (SOD2)-plasmid/liposome treatment 24 h prior to irradiation markedly decreased the mRNA levels of cytokines (IL-1, TNF-α and IFN-γ) in C3H/HeNsd mice and inhibited apoptosis and micro-ulceration (153). Of note, IL-1 and TNF-α pre-treatment protected hematopoietic cells against lethal cytotoxicity from HDIR, mostly through the production of a specific antioxidant enzyme, SOD2 (154). Exogenous IFN-γ and TNF-α were reported to mimic the effects of bone marrow transplantation on the suppression of radiation lymphedema (155). Taken together, the aforementioned findings indicate that Th1 cytokines, such as IFN-γ and TNF-α, markedly promote radiation-related inflammation, but reduce fibrosis, myelosuppression and radiation lymphedema.

5. Conclusion

The modulation of the Th1/Th2 balance in the tumor micro- environment has prominent immunoregulatory properties and interferes with tumor progression. An increasing number of molecular-centric studies indicate that IR may modify the Th1/Th2 shift based on different irradiation doses. The combination of clinically transformable Th1/Th2 modulators and IR at the proper dose and fraction may help design practical and effective antitumor therapies. Hopefully, such treatment will benefit patients with unsatisfactory prognosis and radiation-induced complications via modulating the cross- talk of immunocytes and Th1/Th2 cytokines in the presence of irradiation. Further investigations on the regulatory roles of Th cells in the TIME will improve the comprehensive understanding of the possible applicability of immunoradiotherapy in the treatment of malignant tumors.

Availability of data and materials

Not applicable.

Authors' contributions

JL, ZZ, YG and CX retrieved and summarized the relevant literature and drafted the manuscript. QW, JC, XL and JiZ revised the draft of the manuscript. YL, WS, ZH and JuZ created the figures and tables. YG and CX confirmed the authenticity of all the raw data. All the authors (JL, ZZ, QW, JC, XL, JiZ, YL, WS, ZH, JuZ, YG and CX) contributed to manuscript revision, and have read and approved the final version.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

The authors would like to thank Dr Yingming Sun (Sanming First Hospital) for providing guidance and assistance with the writing of the manuscript.

Funding

The present study was supported by the National Natural Science Foundation of China (grant nos. 81773236, 81800429 and 81972852), the Key Research and Development Project of Hubei Province (grant no. 2020BCA069), the Natural Science Foundation of Hubei Province (grant no. 2020CFB612), Health Commission of Hubei Province Medical Leading Talent Project, Health Commission of Hubei Province Scientific Research Project (grant nos. WJ2019H002 and WJ2019Q047), Young and Middle-Aged Medical Backbone Talents of Wuhan (grant no. WHQG201902), Application Foundation Frontier Project of Wuhan (grant no. 2020020601012221), and Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund (grant nos. znpy2019001, znpy2019048 and ZNJC201922), and the Chinese Society of Clinical Oncology Top Alliance Tumor Immune Research Fund (no. Y-JS2019-036).

References

1 

Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC, et al: Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 24:541–550. 2018. View Article : Google Scholar : PubMed/NCBI

2 

Borst J, Ahrends T, Bąbała N, Melief CJM and Kastenmüller W: CD4+ T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 18:635–647. 2018. View Article : Google Scholar : PubMed/NCBI

3 

Linehan WM and Ricketts CJ: The cancer genome atlas of renal cell carcinoma: Findings and clinical implications. Nat Rev Urol. 16:539–552. 2019. View Article : Google Scholar : PubMed/NCBI

4 

Skinnider BF and Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood. 99:4283–4297. 2002. View Article : Google Scholar : PubMed/NCBI

5 

Liu Z, Fan H and Jiang S: CD4(+) T-cell subsets in transplantation. Immunol Rev. 252:183–191. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Formenti SC and Demaria S: Combining radiotherapy and cancer immunotherapy: A paradigm shift. J Natl Cancer Inst. 105:256–265. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Masjedi A, Hashemi V, Hojjat-Farsangi M, Ghalamfarsa G, Azizi G, Yousefi M and Jadidi-Niaragh F: The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother. 108:1415–1424. 2018. View Article : Google Scholar : PubMed/NCBI

8 

Zhu J and Paul WE: CD4 T cells: Fates, functions, and faults. Blood. 112:1557–1569. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Wan YY: GATA3: A master of many trades in immune regulation. Trends Immunol. 35:233–242. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Maazi H and Akbari O: Type two innate lymphoid cells: The Janus cells in health and disease. Immunol Rev. 278:192–206. 2017. View Article : Google Scholar : PubMed/NCBI

11 

Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy TL and Murphy KM: T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nat Immunol. 3:549–557. 2002. View Article : Google Scholar : PubMed/NCBI

12 

Tian L, Goldstein A, Wang H, Ching Lo H, Sun Kim I, Welte T, Sheng K, Dobrolecki LE, Zhang X, Putluri N, et al: Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature. 544:250–254. 2017. View Article : Google Scholar : PubMed/NCBI

13 

El-Darawish Y, Li W, Yamanishi K, Pencheva M, Oka N, Yamanishi H, Matsuyama T, Tanaka Y, Minato N and Okamura H: Frontline Science: IL-18 primes murine NK cells for proliferation by promoting protein synthesis, survival, and autophagy. J Leukoc Biol. 104:253–264. 2018. View Article : Google Scholar : PubMed/NCBI

14 

Gupta S and Gollapudi S: Molecular mechanisms of TNF-alpha-induced apoptosis in naïve and memory T cell subsets. Autoimmun Rev. 5:264–268. 2006. View Article : Google Scholar : PubMed/NCBI

15 

van Horssen R, Ten Hagen TL and Eggermont AM: TNF-alpha in cancer treatment: Molecular insights, antitumor effects, and clinical utility. Oncologist. 11:397–408. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Vadevoo SMP, Kim JE, Gunassekaran GR, Jung HK, Chi L, Kim DE, Lee SH, Im SH and Lee B: IL4 receptor-targeted proapoptotic peptide blocks tumor growth and metastasis by enhancing antitumor immunity. Mol Cancer Ther. 16:2803–2816. 2017. View Article : Google Scholar : PubMed/NCBI

17 

Oft M: Immune regulation and cytotoxic T cell activation of IL-10 agonists-preclinical and clinical experience. Semin Immunol. 44:1013252019. View Article : Google Scholar

18 

Urosevic M and Dummer R: HLA-G and IL-10 expression in human cancer-different stories with the same message. Semin Cancer Biol. 13:337–342. 2003. View Article : Google Scholar

19 

Sallusto F, Lenig D, Mackay CR and Lanzavecchia A: Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med. 187:875–883. 1998. View Article : Google Scholar : PubMed/NCBI

20 

Annunziato F, Galli G, Cosmi L, Romagnani P, Manetti R, Maggi E and Romagnani S: Molecules associated with human Th1 or Th2 cells. Eur Cytokine Netw. 9(3 Suppl): S12–S16. 1998.

21 

Annunziato F, Manetti R, Tomasévic I, Guidizi MG, Biagiotti R, Giannò V, Germano P, Mavilia C, Maggi E and Romagnani S: Expression and release of LAG-3-encoded protein by human CD4+ T cells are associated with IFN-gamma production. FASEB J. 10:769–776. 1996. View Article : Google Scholar : PubMed/NCBI

22 

Szabo SJ, Dighe AS, Gubler U and Murphy KM: Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med. 185:817–824. 1997. View Article : Google Scholar : PubMed/NCBI

23 

Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C and Dayer JM: CCR5 is characteristic of Th1 lymphocytes. Nature. 391:344–345. 1998. View Article : Google Scholar : PubMed/NCBI

24 

Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B and Mackay CR: The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest. 101:746–754. 1998. View Article : Google Scholar : PubMed/NCBI

25 

Sabatos CA, Chakravarti S, Cha E, Schubart A, Sánchez-Fueyo A, Zheng XX, Coyle AJ, Strom TB, Freeman GJ and Kuchroo VK: Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol. 4:1102–1110. 2003. View Article : Google Scholar : PubMed/NCBI

26 

Xu D, Chan WL, Leung BP, Hunter D, Schulz K, Carter RW, McInnes IB, Robinson JH and Liew FY: Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells. J Exp Med. 188:1485–1492. 1998. View Article : Google Scholar : PubMed/NCBI

27 

D'Ambrosio D, Iellem A, Bonecchi R, Mazzeo D, Sozzani S, Mantovani A and Sinigaglia F: Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J Immunol. 161:5111–5115. 1998.PubMed/NCBI

28 

Cosmi L, Annunziato F, Galli MIG, Maggi RME, Nagata K and Romagnani S: CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease. Eur J Immunol. 30:2972–2979. 2000. View Article : Google Scholar : PubMed/NCBI

29 

Groux H, Sornasse T, Cottrez F, de Vries JE, Coffman RL, Roncarolo MG and Yssel H: Induction of human T helper cell type 1 differentiation results in loss of IFN-gamma receptor beta-chain expression. J Immunol. 158:5627–5631. 1997.PubMed/NCBI

30 

Jourdan P, Abbal C, Noraz N, Hori T, Uchiyama T, Vendrell JP, Bousquet J, Taylor N, Pène J and Yssel H: IL-4 induces functional cell-surface expression of CXCR4 on human T cells. J Immunol. 160:4153–4157. 1998.PubMed/NCBI

31 

Xu D, Chan WL, Leung BP, Huang Fp, Wheeler R, Piedrafita D, Robinson JH and Liew FY: Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J Exp Med. 187:787–794. 1998. View Article : Google Scholar : PubMed/NCBI

32 

Del Prete G, De Carli M, D'Elios MM, Daniel KC, Almerigogna F, Alderson M, Smith CA, Thomas E and Romagnani S: CD30-mediated signaling promotes the development of human T helper type 2-like T cells. J Exp Med. 182:1655–1661. 1995. View Article : Google Scholar : PubMed/NCBI

33 

Sallusto F, Mackay CR and Lanzavecchia A: Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science. 277:2005–2007. 1997. View Article : Google Scholar : PubMed/NCBI

34 

Weinstein JS, Laidlaw BJ, Lu Y, Wang JK, Schulz VP, Li N, Herman EI, Kaech SM, Gallagher PG and Craft J: STAT4 and T-bet control follicular helper T cell development in viral infections. J Exp Med. 215:337–355. 2018. View Article : Google Scholar :

35 

Christodoulopoulos P, Cameron L, Nakamura Y, Lemière C, Muro S, Dugas M, Boulet LP, Laviolette M, Olivenstein R and Hamid Q: TH2 cytokine-associated transcription factors in atopic and nonatopic asthma: Evidence for differential signal transducer and activator of transcription 6 expression. J Allergy Clin Immunol. 107:586–591. 2001. View Article : Google Scholar : PubMed/NCBI

36 

Zheng W and Flavell RA: The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 89:587–596. 1997. View Article : Google Scholar : PubMed/NCBI

37 

Kaplan MH, Schindler U, Smiley ST and Grusby MJ: Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 4:313–319. 1996. View Article : Google Scholar : PubMed/NCBI

38 

Ho IC, Hodge MR, Rooney JW and Glimcher LH: The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell. 85:973–983. 1996. View Article : Google Scholar : PubMed/NCBI

39 

Han SK, Song JY, Yun YS and Yi SY: Effect of gamma radiation on cytokine expression and cytokine-receptor mediated STAT activation. Int J Radiat Biol. 82:686–697. 2006. View Article : Google Scholar : PubMed/NCBI

40 

Ridnour LA, Cheng RY, Weiss JM, Kaur S, Soto-Pantoja DR, Basudhar D, Heinecke JL, Stewart CA, DeGraff W, Sowers AL, et al: NOS inhibition modulates immune polarization and improves radiation-induced tumor growth delay. Cancer Res. 75:2788–2799. 2015. View Article : Google Scholar : PubMed/NCBI

41 

Attar M, Molaie Kondolousy Y and Khansari N: Effect of high dose natural ionizing radiation on the immune system of the exposed residents of Ramsar Town, Iran. Iran J Allergy Asthma Immunol. 6:73–78. 2007.PubMed/NCBI

42 

Karkanitsa L, Mitskevitch P, Uss A, Ostapenko V and Dainiak N: Elevated levels of cytokine gene expression in leukemic hemopoietic cells of belorussians exposed to ionizing radiation (IR) following the chernobyl catastrophe. Blood. 96:295A2000.

43 

Han SK, Song JY, Yun YS and Yi SY: Ginsan improved Th1 immune response inhibited by gamma radiation. Arch Pharm Res. 28:343–350. 2005. View Article : Google Scholar : PubMed/NCBI

44 

Kunwar A, Bag PP, Chattopadhyay S, Jain VK and Priyadarsini KI: Anti-apoptotic, anti-inflammatory, and immunomodulatory activities of 3,3′-diselenodipropionic acid in mice exposed to whole body γ-radiation. Arch Toxicol. 85:1395–1405. 2011. View Article : Google Scholar : PubMed/NCBI

45 

Liu H, Li B, Jia X, Ma Y, Gu Y, Zhang P, Wei Q, Cai J, Cui J, Gao F and Yang Y: Radiation-induced decrease of CD8+ dendritic cells contributes to Th1/Th2 shift. Int Immunopharmacol. 46:178–185. 2017. View Article : Google Scholar : PubMed/NCBI

46 

Mishra S, Patel DD, Bansal DD and Kumar R: Semiquinone glucoside derivative provides protection against γ-radiation by modulation of immune response in murine model. Environ Toxicol. 31:478–488. 2016. View Article : Google Scholar

47 

Malhotra P, Adhikari M, Mishra S, Singh S, Kumar P, Singh SK and Kumar R: N-acetyl tryptophan glucopyranoside (NATG) as a countermeasure against gamma radiation-induced immunosuppression in murine macrophage J774A.1 cells. Free Radic Res. 50:1265–1278. 2016. View Article : Google Scholar : PubMed/NCBI

48 

Nadella V, Ranjan R, Senthilkumaran B, Qadri SSYH, Pothani S, Singh AK, Gupta ML and Prakash H: Podophyllotoxin and rutin modulate M1 (iNOS+) macrophages and mitigate lethal radiation (LR) induced inflammatory responses in mice. Front Immunol. 10:1062019. View Article : Google Scholar : PubMed/NCBI

49 

Liu XD, Ma SM and Liu SZ: Effects of 0.075 Gy x-ray irradiation on the expression of IL-10 and IL-12 in mice. Phys Med Biol. 48:2041–2049. 2003. View Article : Google Scholar : PubMed/NCBI

50 

Gao H, Dong Z, Gong X, Dong J, Zhang Y, Wei W, Wang R and Jin S: Effects of various radiation doses on induced T-helper cell differentiation and related cytokine secretion. J Radiat Res. 59:395–403. 2018. View Article : Google Scholar : PubMed/NCBI

51 

Karimi G, Balali-Mood M, Alamdaran SA, Badie-Bostan H, Mohammadi E, Ghorani-Azam A, Sadeghi M and Riahi-Zanjani B: Increase in the Th1-cell-based immune response in healthy workers exposed to low-dose radiation-immune system status of radiology staff. J Pharmacopuncture. 20:107–111. 2017.PubMed/NCBI

52 

Cho SJ, Kang H, Hong EH, Kim JY and Nam SY: Transcriptome analysis of low-dose ionizing radiation-impacted genes in CD4+ T-cells undergoing activation and regulation of their expression of select cytokines. J Immunotoxicol. 15:137–146. 2018. View Article : Google Scholar

53 

Bogdándi EN, Balogh A, Felgyinszki N, Szatmári T, Persa E, Hildebrandt G, Sáfrány G and Lumniczky K: Effects of low-dose radiation on the immune system of mice after total-body irradiation. Radiat Res. 174:480–489. 2010. View Article : Google Scholar : PubMed/NCBI

54 

Elhadary AA, Marzook EA and Abdelmonem HA: Evaluation of the level of gamma radiation dose on some immune system parameters against cancer. Biosci J. 35:307–316. 2019. View Article : Google Scholar

55 

Ghazy AA, Abu El-Nazar SY, Ghoneim HE, Taha AR and Abouelella AM: Effect of murine exposure to gamma rays on the interplay between Th1 and Th2 lymphocytes. Front Pharmacol. 6:742015. View Article : Google Scholar : PubMed/NCBI

56 

Liu X, Liu Z, Wang D, Han Y, Hu S, Xie Y, Liu Y, Zhu M, Guan H, Gu Y and Zhou PK: Effects of low dose radiation on immune cells subsets and cytokines in mice. Toxicol Res (Camb). 9:249–262. 2020. View Article : Google Scholar

57 

Steinman RM: Decisions about dendritic cells: Past, present, and future. Annu Rev Immunol. 30:1–22. 2012. View Article : Google Scholar

58 

Arpinati M, Green CL, Heimfeld S, Heuser JE and Anasetti C: Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood. 95:2484–2490. 2000. View Article : Google Scholar

59 

Jutel M and Akdis CA: T-cell subset regulation in atopy. Curr Allergy Asthma Rep. 11:139–145. 2011. View Article : Google Scholar : PubMed/NCBI

60 

Merrick A, Errington F, Milward K, O'Donnell D, Harrington K, Bateman A, Pandha H, Vile R, Morrison E, Selby P and Melcher A: Immunosuppressive effects of radiation on human dendritic cells: Reduced IL-12 production on activation and impairment of naive T-cell priming. Br J Cancer. 92:1450–1458. 2005. View Article : Google Scholar : PubMed/NCBI

61 

Clerici M, Shearer GM and Clerici E: Cytokine dysregulation in invasive cervical carcinoma and other human neoplasias: Time to consider the TH1/TH2 paradigm. J Natl Cancer Inst. 90:261–263. 1998. View Article : Google Scholar : PubMed/NCBI

62 

Lappin MB and Campbell JD: The Th1-Th2 classification of cellular immune responses: Concepts, current thinking and applications in haematological malignancy. Blood Rev. 14:228–239. 2000. View Article : Google Scholar : PubMed/NCBI

63 

Backer RA, Diener N and Clausen BE: Langerin+CD8+ dendritic cells in the splenic marginal zone: Not so marginal after all. Front Immunol. 10:7412019. View Article : Google Scholar

64 

Prendergast KA, Daniels NJ, Petersen TR, Hermans IF and Kirman JR: Langerin+ CD8α+ dendritic cells drive early CD8+ T cell activation and IL-12 production during systemic bacterial infection. Front Immunol. 9:9532018. View Article : Google Scholar

65 

Yu N, Wang S, Song X, Gao L, Li W, Yu H, Zhou C, Wang Z, Li F and Jiang Q: Low-dose radiation promotes dendritic cell migration and IL-12 production via the ATM/NF-kappaB pathway. Radiat Res. 189:409–417. 2018. View Article : Google Scholar : PubMed/NCBI

66 

Shigematsu A, Adachi Y, Koike-Kiriyama N, Suzuki Y, Iwasaki M, Koike Y, Nakano K, Mukaide H, Imamura M and Ikehara S: Effects of low-dose irradiation on enhancement of immunity by dendritic cells. J Radiat Res. 48:51–55. 2007. View Article : Google Scholar

67 

Murray PJ: Macrophage polarization. Annu Rev Physiol. 79:541–566. 2017. View Article : Google Scholar

68 

Orecchioni M, Ghosheh Y, Pramod AB and Ley K: Macrophage polarization: Different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages. Front Immunol. 10:10842019. View Article : Google Scholar : PubMed/NCBI

69 

Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, Seifi B, Mohammadi A, Afshari JT and Sahebkar A: Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 233:6425–6440. 2018. View Article : Google Scholar : PubMed/NCBI

70 

Shiratori H, Feinweber C, Luckhardt S, Wallner N, Geisslinger G, Weigert A and Parnham MJ: An in vitro test system for compounds that modulate human inflammatory macrophage polarization. Eur J Pharmacol. 833:328–338. 2018. View Article : Google Scholar : PubMed/NCBI

71 

Nadella V, Singh S, Jain A, Jain M, Vasquez KM, Sharma A, Tanwar P, Rath GK and Prakash H: Low dose radiation primed iNOS + M1macrophages modulate angiogenic programming of tumor derived endothelium. Mol Carcinog. 57:1664–1671. 2018. View Article : Google Scholar : PubMed/NCBI

72 

Knoops L, Haas R, de Kemp S, Majoor D, Broeks A, Eldering E, de Boer JP, Verheij M, van Ostrom C, de Vries A, et al: In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma. Blood. 110:1116–1122. 2007. View Article : Google Scholar : PubMed/NCBI

73 

Seifert L, Werba G, Tiwari S, Giao Ly NN, Nguy S, Alothman S, Alqunaibit D, Avanzi A, Daley D, Barilla R, et al: Radiation therapy induces macrophages to suppress T-cell responses against pancreatic tumors in mice. Gastroenterology. 150:1659–1672.e5. 2016. View Article : Google Scholar : PubMed/NCBI

74 

Okubo M, Kioi M, Nakashima H, Sugiura K, Mitsudo K, Aoki I, Taniguchi H and Tohnai I: M2-polarized macrophages contribute to neovasculogenesis, leading to relapse of oral cancer following radiation. Sci Rep. 6:275482016. View Article : Google Scholar : PubMed/NCBI

75 

Fu E, Liu T, Yu S, Chen X, Song L, Lou H, Ma F, Zhang S, Hussain S, Guo J, et al: M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB-EGF. Oncol Rep. 44:698–710. 2020. View Article : Google Scholar : PubMed/NCBI

76 

Reading JL, Gálvez-Cancino F, Swanton C, Lladser A, Peggs KS and Quezada SA: The function and dysfunction of memory CD8+ T cells in tumor immunity. Immunol Rev. 283:194–212. 2018. View Article : Google Scholar : PubMed/NCBI

77 

Crespo J, Sun H, Welling TH, Tian Z and Zou W: T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 25:214–221. 2013. View Article : Google Scholar : PubMed/NCBI

78 

Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, et al: Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: Changing strategies for cancer treatment. Blood. 114:589–595. 2009. View Article : Google Scholar : PubMed/NCBI

79 

Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG and Lord EM: Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 174:7516–7523. 2005. View Article : Google Scholar : PubMed/NCBI

80 

Takeshima T, Chamoto K, Wakita D, Ohkuri T, Togashi Y, Shirato H, Kitamura H and Nishimura T: Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: Its potentiation by combination with Th1 cell therapy. Cancer Res. 70:2697–2706. 2010. View Article : Google Scholar : PubMed/NCBI

81 

Chattopadhyay S and Chakraborty NG: Continuous presence of Th1 conditions is necessary for longer lasting tumor-specific CTL activity in stimulation cultures with PBL. Hum Immunol. 66:884–891. 2005. View Article : Google Scholar : PubMed/NCBI

82 

Harada M, Matsueda S, Yao A, Noguchi M and Itoh K: Vaccination of cytotoxic T lymphocyte-directed peptides elicited and spread humoral and Th1-type immune responses to prostate-specific antigen protein in a prostate cancer patient. J Immunother. 28:368–375. 2005. View Article : Google Scholar : PubMed/NCBI

83 

Yokouchi H, Chamoto K, Wakita D, Yamazaki K, Shirato H, Takeshima T, Dosaka-Akita H, Nishimura M, Yue Z, Kitamura H and Nishimura T: Combination tumor immunotherapy with radiotherapy and Th1 cell therapy against murine lung carcinoma. Clin Exp Metastasis. 24:533–540. 2007. View Article : Google Scholar : PubMed/NCBI

84 

Terrén I, Orrantia A, Vitallé J, Zenarruzabeitia O and Borrego F: NK cell metabolism and tumor microenvironment. Front Immunol. 10:22782019. View Article : Google Scholar : PubMed/NCBI

85 

Hodgins JJ, Khan ST, Park MM, Auer RC and Ardolino M: Killers 2.0: NK cell therapies at the forefront of cancer control. J Clin Invest. 129:3499–3510. 2019. View Article : Google Scholar : PubMed/NCBI

86 

Wei H, Zheng X, Lou D, Zhang L, Zhang R, Sun R and Tian Z: Tumor-induced suppression of interferon-gamma production and enhancement of interleukin-10 production by natural killer (NK) cells: Paralleled to CD4+ T cells. Mol Immunol. 42:1023–1031. 2005. View Article : Google Scholar : PubMed/NCBI

87 

Yang G, Kong Q, Wang G, Jin H, Zhou L, Yu D, Niu C, Han W, Li W and Cui J: Low-dose ionizing radiation induces direct activation of natural killer cells and provides a novel approach for adoptive cellular immunotherapy. Cancer Biother Radiopharm. 29:428–434. 2014. View Article : Google Scholar : PubMed/NCBI

88 

Cheda A, Wrembel-Wargocka J, Lisiak E, Nowosielska EM, Marciniak M and Janiak MK: Single low doses of X rays inhibit the development of experimental tumor metastases and trigger the activities of NK cells in mice. Radiat Res. 161:335–340. 2004. View Article : Google Scholar : PubMed/NCBI

89 

Miller GM, Andres ML and Gridley DS: NK cell depletion results in accelerated tumor growth and attenuates the antitumor effect of total body irradiation. Int J Oncol. 23:1585–1592. 2003.PubMed/NCBI

90 

Park HR, Jung U and Jo SK: Impairment of natural killer (NK) cells is an important factor in a weak Th1-like response in irradiated mice. Radiat Res. 168:446–452. 2007. View Article : Google Scholar : PubMed/NCBI

91 

Zarcone D, Tilden AB, Lane VG and Grossi CE: Radiation sensitivity of resting and activated nonspecific cytotoxic cells of T lineage and NK lineage. Blood. 73:1615–1621. 1989. View Article : Google Scholar : PubMed/NCBI

92 

Zhou L, Zhang X, Li H, Niu C, Yu D, Yang G, Liang X, Wen X, Li M and Cui J: Validating the pivotal role of the immune system in low-dose radiation-induced tumor inhibition in Lewis lung cancer-bearing mice. Cancer Med. 7:1338–1348. 2018. View Article : Google Scholar : PubMed/NCBI

93 

Zhou J, Zhang J, Lichtenheld MG and Meadows GG: A role for NF-kappa B activation in perforin expression of NK cells upon IL-2 receptor signaling. J Immunol. 169:1319–1325. 2002. View Article : Google Scholar : PubMed/NCBI

94 

Herrera FG, Bourhis J and Coukos G: Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin. 67:65–85. 2017. View Article : Google Scholar

95 

Demaria S, Golden EB and Formenti SC: Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. 1:1325–1332. 2015. View Article : Google Scholar : PubMed/NCBI

96 

Simon PS, Bardhan K, Chen MR, Paschall AV, Lu C, Bollag RJ, Kong FC, Jin J, Kong FM, Waller JL, et al: NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression. Oncotarget. 7:23395–23415. 2016. View Article : Google Scholar : PubMed/NCBI

97 

Matsumura S, Wang B, Kawashima N, Braunstein S, Badura M, Cameron TO, Babb JS, Schneider RJ, Formenti SC, Dustin ML and Demaria S: Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol. 181:3099–3107. 2008. View Article : Google Scholar : PubMed/NCBI

98 

Song KH, Jung SY, Kang SM, Kim MH, Ahn J, Hwang SG, Lee JH, Lim DS, Nam SY and Song JY: Induction of immunogenic cell death by radiation-upregulated karyopherin alpha 2 in vitro. Eur J Cell Biol. 95:219–227. 2016. View Article : Google Scholar : PubMed/NCBI

99 

Song KH, Jung SY, Park JI, Ahn J, Park JK, Um HD, Park IC, Hwang SG, Ha H and Song JY: Inhibition of karyopherin-α2 augments radiation-induced cell death by perturbing BRCA1-mediated DNA repair. Int J Mol Sci. 20:28432019. View Article : Google Scholar

100 

Huettner C, Paulus W and Roggendorf W: Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am J Pathol. 146:317–322. 1995.PubMed/NCBI

101 

Hao C, Parney IF, Roa WH, Turner J, Petruk KC and Ramsay DA: Cytokine and cytokine receptor mRNA expression in human glioblastomas: Evidence of Th1, Th2 and Th3 cytokine dysregulation. Acta Neuropathol. 103:171–178. 2002. View Article : Google Scholar : PubMed/NCBI

102 

Chen B, Alvarado DM, Iticovici M, Kau NS, Park H, Parikh PJ, Thotala D and Ciorba MA: Interferon-induced IDO1 mediates radiation resistance and is a therapeutic target in colorectal cancer. Cancer Immunol Res. 8:451–464. 2020. View Article : Google Scholar : PubMed/NCBI

103 

Hanania AN, Mainwaring W, Ghebre YT, Hanania NA and Ludwig M: Radiation-induced lung injury: Assessment and management. Chest. 156:150–162. 2019. View Article : Google Scholar : PubMed/NCBI

104 

Giuranno L, Ient J, De Ruysscher D and Vooijs MA: Radiation-induced lung injury (RILI). Front Oncol. 9:8772019. View Article : Google Scholar : PubMed/NCBI

105 

Stenmark MH, Cai XW, Shedden K, Hayman JA, Yuan S, Ritter T, Ten Haken RK, Lawrence TS and Kong FM: Combining physical and biologic parameters to predict radiation-induced lung toxicity in patients with non-small-cell lung cancer treated with definitive radiation therapy. Int J Radiat Oncol Biol Phys. 84:e217–e222. 2012. View Article : Google Scholar : PubMed/NCBI

106 

Rübe CE, Rodemann HP and Rübe C: The relevance of cytokines in the radiation-induced lung reaction. Experimental basis and clinical significance. Strahlenther Onkol. 180:541–549. 2004.In German. View Article : Google Scholar

107 

Arpin D, Perol D, Blay JY, Falchero L, Claude L, Vuillermoz-Blas S, Martel-Lafay I, Ginestet C, Alberti L, Nosov D, et al: Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis. J Clin Oncol. 23:8748–8756. 2005. View Article : Google Scholar : PubMed/NCBI

108 

Büttner C, Skupin A, Reimann T, Rieber EP, Unteregger G, Geyer P and Frank KH: Local production of interleukin-4 during radiation-induced pneumonitis and pulmonary fibrosis in rats: Macrophages as a prominent source of interleukin-4. Am J Respir Cell Mol Biol. 17:315–325. 1997. View Article : Google Scholar : PubMed/NCBI

109 

Chen Y, Rubin P, Williams J, Hernady E, Smudzin T and Okunieff P: Circulating IL-6 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 49:641–648. 2001. View Article : Google Scholar : PubMed/NCBI

110 

Tang Y, Yang L, Qin W, Yi M, Liu B and Yuan X: Validation study of the association between genetic variant of IL4 and severe radiation pneumonitis in lung cancer patients treated with radiation therapy. Radiother Oncol. 141:86–94. 2019. View Article : Google Scholar : PubMed/NCBI

111 

Li Y, Guan X, Liu W, Chen HL, Truscott J, Beyatli S, Metwali A, Weiner GJ, Zavazava N, Blumberg RS, et al: Helminth-induced production of TGF-β and suppression of graft-versus-host disease is dependent on IL-4 production by host cells. J Immunol. 201:2910–2922. 2018. View Article : Google Scholar : PubMed/NCBI

112 

Groves AM, Johnston CJ, Misra RS, Williams JP and Finkelstein JN: Effects of IL-4 on pulmonary fibrosis and the accumulation and phenotype of macrophage subpopulations following thoracic irradiation. Int J Radiat Biol. 92:754–765. 2016. View Article : Google Scholar : PubMed/NCBI

113 

Han G, Zhang H, Xie CH and Zhou YF: Th2-like immune response in radiation-induced lung fibrosis. Oncol Rep. 26:383–388. 2011.PubMed/NCBI

114 

Paun A, Bergeron ME and Haston CK: The Th1/Th17 balance dictates the fibrosis response in murine radiation-induced lung disease. Sci Rep. 7:115862017. View Article : Google Scholar : PubMed/NCBI

115 

Xu L, Xiong S, Guo R, Yang Z, Wang Q, Xiao F, Wang H, Pan X and Zhu M: Transforming growth factor β3 attenuates the development of radiation-induced pulmonary fibrosis in mice by decreasing fibrocyte recruitment and regulating IFN-gamma/IL-4 balance. Immunol Lett. 162:27–33. 2014. View Article : Google Scholar : PubMed/NCBI

116 

Chiang CS, Liu WC, Jung SM, Chen FH, Wu CR, McBride WH, Lee CC and Hong JH: Compartmental responses after thoracic irradiation of mice: Strain differences. Int J Radiat Oncol Biol Phys. 62:862–871. 2005. View Article : Google Scholar : PubMed/NCBI

117 

Zhang C, Zhao H, Li BL, Fu-Gao, Liu H, Cai JM and Zheng M: CpG-oligodeoxynucleotides may be effective for preventing ionizing radiation induced pulmonary fibrosis. Toxicol Lett. 292:181–189. 2018. View Article : Google Scholar : PubMed/NCBI

118 

Huang Y, Liu W, Liu H, Yang Y, Cui J, Zhang P, Zhao H, He F, Cheng Y, Ni J, et al: Grape seed pro-anthocyanidins ameliorates radiation-induced lung injury. J Cell Mol Med. 18:1267–1277. 2014. View Article : Google Scholar : PubMed/NCBI

119 

Chen J, Wang Y, Mei Z, Zhang S, Yang J, Li X, Yao Y and Xie C: Radiation-induced lung fibrosis in a tumor-bearing mouse model is associated with enhanced Type-2 immunity. J Radiat Res. 57:133–141. 2016. View Article : Google Scholar :

120 

Oh K, Seo MW, Kim YW and Lee DS: Osteopontin potentiates pulmonary inflammation and fibrosis by modulating IL-17/IFN-γ-secreting T-cell ratios in bleomycin-treated mice. Immune Netw. 15:142–149. 2015. View Article : Google Scholar : PubMed/NCBI

121 

Lei L, Zhao C, Qin F, He ZY, Wang X and Zhong XN: Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis. Clin Exp Rheumatol. 34(Suppl 100): S14–S22. 2016.

122 

Li Y, Zou L, Yang X, Chu L, Ni J, Chu X, Guo T and Zhu Z: Identification of lncRNA, MicroRNA, and mRNA-associated CeRNA network of radiation-induced lung injury in a mice model. Dose Response. 17:15593258198910122019. View Article : Google Scholar : PubMed/NCBI

123 

Hauer-Jensen M, Denham JW and Andreyev HJ: Radiation enteropathy-pathogenesis, treatment and prevention. Nat Rev Gastroenterol Hepatol. 11:470–479. 2014. View Article : Google Scholar : PubMed/NCBI

124 

Zheng J, Wang J, Pouliot M, Authier S, Zhou D, Loose DS and Hauer-Jensen M: Gene expression profiling in non-human primate jejunum, ileum and colon after total-body irradiation: A comparative study of segment-specific molecular and cellular responses. BMC Genomics. 16:9842015. View Article : Google Scholar : PubMed/NCBI

125 

Huang Z, Epperly M, Watkins SC, Greenberger JS, Kagan VE and Bayır H: Necrostatin-1 rescues mice from lethal irradiation. Biochim Biophys Acta. 1862:850–856. 2016. View Article : Google Scholar : PubMed/NCBI

126 

Kim JS, Ryoo SB, Heo K, Kim JG, Son TG, Moon C and Yang K: Attenuating effects of granulocyte-colony stimulating factor (G-CSF) in radiation induced intestinal injury in mice. Food Chem Toxicol. 50:3174–3180. 2012. View Article : Google Scholar : PubMed/NCBI

127 

Kim JS, Yang M, Lee CG, Kim SD, Kim JK and Yang K: In vitro and in vivo protective effects of granulocyte colony-stimulating factor against radiation-induced intestinal injury. Arch Pharm Res. 36:1252–1261. 2013. View Article : Google Scholar : PubMed/NCBI

128 

Symon Z, Goldshmidt Y, Picard O, Yavzori M, Ben-Horin S, Alezra D, Barshack I and Chowers Y: A murine model for the study of molecular pathogenesis of radiation proctitis. Int J Radiat Oncol Biol Phys. 76:242–250. 2010. View Article : Google Scholar

129 

Sha H, Gu Y, Shen W, Zhang L, Qian F, Zhao Y, Li H, Zhang T and Lu W: Rheinic acid ameliorates radiation-induced acute enteritis in rats through PPAR-γ/NF-κB. Genes Genomics. 41:909–917. 2019. View Article : Google Scholar : PubMed/NCBI

130 

Lu L, Li W, Sun C, Kang S, Li J, Luo X, Su Q, Liu B and Qin S: Phycocyanin ameliorates radiation-induced acute intestinal toxicity by regulating the effect of the gut microbiota on the TLR4/Myd88/NF-κB pathway. JPEN J Parenter Enteral Nutr. 44:1308–1317. 2020. View Article : Google Scholar

131 

Wei YL, Xu JY, Zhang R, Zhang Z, Zhao L and Qin LQ: Effects of lactoferrin on X-ray-induced intestinal injury in Balb/C mice. Appl Radiat Isot. 146:72–77. 2019. View Article : Google Scholar : PubMed/NCBI

132 

Radwan RR and Karam HM: Resveratrol attenuates intestinal injury in irradiated rats via PI3K/Akt/mTOR signaling pathway. Environ Toxicol. 35:223–230. 2020. View Article : Google Scholar

133 

Wang H, Sun RT, Li Y, Yang YF, Xiao FJ, Zhang YK, Wang SX, Sun HY, Zhang QW, Wu CT and Wang LS: HGF gene modification in mesenchymal stem cells reduces radiation-induced intestinal injury by modulating immunity. PLoS One. 10:e01244202015. View Article : Google Scholar : PubMed/NCBI

134 

Chang P, Qu Y, Liu Y, Cui S, Zhu D, Wang H and Jin X: Multi-therapeutic effects of human adipose-derived mesenchymal stem cells on radiation-induced intestinal injury. Cell Death Dis. 4:e6852013. View Article : Google Scholar : PubMed/NCBI

135 

Linard C, Strup-Perrot C, Lacave-Lapalun JV and Benderitter M: Flagellin preconditioning enhances the efficacy of mesenchymal stem cells in an irradiation-induced proctitis model. J Leukoc Biol. 100:569–580. 2016. View Article : Google Scholar : PubMed/NCBI

136 

Akpolat M, Gulle K, Topcu-Tarladacalisir Y, Safi Oz Z, Bakkal BH, Arasli M and Ozel Turkcu U: Protection by L-carnitine against radiation-induced ileal mucosal injury in the rat: Pattern of oxidative stress, apoptosis and cytokines. Int J Radiat Biol. 89:732–740. 2013. View Article : Google Scholar : PubMed/NCBI

137 

Bessout R, Demarquay C, Moussa L, René A, Doix B, Benderitter M, Sémont A and Mathieu N: TH17 predominant T-cell responses in radiation-induced bowel disease are modulated by treatment with adipose-derived mesenchymal stromal cells. J Pathol. 237:435–446. 2015. View Article : Google Scholar : PubMed/NCBI

138 

Balentova S and Adamkov M: Molecular, cellular and functional effects of radiation-induced brain injury: A review. Int J Mol Sci. 16:27796–27815. 2015. View Article : Google Scholar : PubMed/NCBI

139 

Deng Z, Sui G, Rosa PM and Zhao W: Radiation-induced c-Jun activation depends on MEK1-ERK1/2 signaling pathway in microglial cells. PLoS One. 7:e367392012. View Article : Google Scholar : PubMed/NCBI

140 

Xue J, Dong JH, Huang GD, Qu XF, Wu G and Dong XR: NF-κB signaling modulates radiation-induced microglial activation. Oncol Rep. 31:2555–2560. 2014. View Article : Google Scholar : PubMed/NCBI

141 

Dong X, Luo M, Huang G, Zhang J, Tong F, Cheng Y, Cai Q, Dong J, Wu G and Cheng J: Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of mice. Int J Radiat Biol. 91:224–239. 2015. View Article : Google Scholar

142 

Chen LJ, Zhang RG, Yu DD, Wu G and Dong XR: Shenqi fuzheng injection ameliorates radiation-induced brain injury. Curr Med Sci. 39:965–971. 2019. View Article : Google Scholar : PubMed/NCBI

143 

Xin N, Li YJ, Li X, Wang X, Li Y, Zhang X, Dai RJ, Meng WW, Wang HL, Ma H, et al: Dragon's blood may have radioprotective effects in radiation-induced rat brain injury. Radiat Res. 178:75–85. 2012. View Article : Google Scholar : PubMed/NCBI

144 

Chiang CS, Hong JH, Stalder A, Sun JR, Withers HR and McBride WH: Delayed molecular responses to brain irradiation. Int J Radiat Biol. 72:45–53. 1997. View Article : Google Scholar : PubMed/NCBI

145 

Vozenin-Brotons MC, Gault N, Sivan V, Tricaud Y, Dubray B, Clough K, Cosset JM, Lefaix JL and Martin M: Histopathological and cellular studies of a case of cutaneous radiation syndrome after accidental chronic exposure to a cesium source. Radiat Res. 152:332–337. 1999. View Article : Google Scholar : PubMed/NCBI

146 

Lee JW, Zoumalan RA, Valenzuela CD, Nguyen PD, Tutela JP, Roman BR, Warren SM and Saadeh PB: Regulators and mediators of radiation-induced fibrosis: Gene expression profiles and a rationale for Smad3 inhibition. Otolaryngol Head Neck Surg. 143:525–530. 2010. View Article : Google Scholar : PubMed/NCBI

147 

Blétry O and Somogyi A: Do the interferons have an antifibrotic action? The internist's point of view. Rev Med Interne. 23(Suppl 4): 511s–515s. 2002.In French. View Article : Google Scholar

148 

Peter RU, Gottlöber P, Nadeshina N, Krähn G, Braun-Falco O and Plewig G: Interferon gamma in survivors of the Chernobyl power plant accident: New therapeutic option for radiation-induced fibrosis. Int J Radiat Oncol Biol Phys. 45:147–152. 1999. View Article : Google Scholar : PubMed/NCBI

149 

Oliva D, Nilsson M, Strandéus M, Andersson BÅ, Sharp L, Laytragoon-Lewin N and Lewin F: Individual genetic variation might predict acute skin reactions in women undergoing adjuvant breast cancer radiotherapy. Anticancer Res. 38:6763–6770. 2018. View Article : Google Scholar : PubMed/NCBI

150 

Takeda I, Kizu Y, Yoshitaka O, Saito I and Yamane GY: Possible role of nitric oxide in radiation-induced salivary gland dysfunction. Radiat Res. 159:465–470. 2003. View Article : Google Scholar : PubMed/NCBI

151 

Moura JF, Mota JM, Leite CA, Wong DV, Bezerra NP, Brito GA, Lima V, Cunha FQ and Ribeiro RA: A novel model of megavoltage radiation-induced oral mucositis in hamsters: Role of inflammatory cytokines and nitric oxide. Int J Radiat Biol. 91:500–509. 2015. View Article : Google Scholar : PubMed/NCBI

152 

Chung YL, Lee MY and Pui NN: Epigenetic therapy using the histone deacetylase inhibitor for increasing therapeutic gain in oral cancer: Prevention of radiation-induced oral mucositis and inhibition of chemical-induced oral carcinogenesis. Carcinogenesis. 30:1387–1397. 2009. View Article : Google Scholar : PubMed/NCBI

153 

Epperly MW, Gretton JA, DeFilippi SJ, Greenberger JS, Sikora CA, Liggitt D and Koe G: Modulation of radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutase-plasmid/liposome (SOD2-PL) gene therapy. Radiat Res. 155:2–14. 2001. View Article : Google Scholar

154 

Moreb J and Zucali JR: The therapeutic potential of interleukin-1 and tumor necrosis factor on hematopoietic stem cells. Leuk Lymphoma. 8:267–275. 1992. View Article : Google Scholar : PubMed/NCBI

155 

Boniver J, Humblet C, Rongy AM, Delvenne C, Delvenne P, Greimers R, Thiry A, Courtoy R and Defresne MP: Cellular aspects of the pathogenesis of radiation-induced thymic lymphomas in C57 BL mice (review). In Vivo. 4:41–43. 1990.PubMed/NCBI

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Spandidos Publications style
Li J, Zeng Z, Wu Q, Chen J, Liu X, Zhang J, Luo Y, Sun W, Huang Z, Zhang J, Zhang J, et al: Immunological modulation of the Th1/Th2 shift by ionizing radiation in tumors (Review). Int J Oncol 59: 50, 2021
APA
Li, J., Zeng, Z., Wu, Q., Chen, J., Liu, X., Zhang, J. ... Xie, C. (2021). Immunological modulation of the Th1/Th2 shift by ionizing radiation in tumors (Review). International Journal of Oncology, 59, 50. https://doi.org/10.3892/ijo.2021.5230
MLA
Li, J., Zeng, Z., Wu, Q., Chen, J., Liu, X., Zhang, J., Luo, Y., Sun, W., Huang, Z., Zhang, J., Gong, Y., Xie, C."Immunological modulation of the Th1/Th2 shift by ionizing radiation in tumors (Review)". International Journal of Oncology 59.1 (2021): 50.
Chicago
Li, J., Zeng, Z., Wu, Q., Chen, J., Liu, X., Zhang, J., Luo, Y., Sun, W., Huang, Z., Zhang, J., Gong, Y., Xie, C."Immunological modulation of the Th1/Th2 shift by ionizing radiation in tumors (Review)". International Journal of Oncology 59, no. 1 (2021): 50. https://doi.org/10.3892/ijo.2021.5230