Advances of the interleukin‑21 signaling pathway in immunity and angiogenesis (Review)

  • Authors:
    • Ming‑Jie Yuan
    • Tao Wang
  • View Affiliations

  • Published online on: April 27, 2016
  • Pages: 3-6
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Interleukin‑21 (IL‑21) and its receptor (IL‑21R) are broadly expressed on human B cells, activated T cells and other myeloid cells. IL‑21 cooperates with IL‑6 and transforming growth factor‑β to regulate T‑cell differentiation. IL‑21‑mediated human B cell and dendritic cells differentiation requires signal transducer and activator of transcription 3 (STAT3), and also induces B‑cell apoptosis dependents on the Toll‑like receptor signal. Recently, in vitro and in vivo experiments showed that IL‑21/IL‑21R regulate angiogenesis through STAT3. IL‑21 signaling pathways are complex due to its cooperation with other transcriptional factors, such as interferon regulatory factor 4 and granulocyte‑macrophage colony‑stimulating factor. The Janus kinase‑STAT pathway has been the most extensively studied. With the increase in the understanding of IL‑21 biology in the context of each specific disease or pathological condition, IL‑21 could be a new therapeutic target for immune‑related disease.


Interleukin-21 (IL-21) and its receptor (IL-21R) were identified in 2000 (1). IL-21 is primarily produced by cluster of differentiation 4+ (CD4+) cells and natural killer cells, while IL-21R is broadly expressed on human B cells, activated T cells and other myeloid cells (2,3). IL-21 is a pleiotrophic cytokine that is composed of four α-helical bundles. IL-21R shares the common cytokines receptor γ chain (γc) with the IL-2 family cytokines, such as IL-4, IL-7, IL-9 and IL-15 (4). In addition, IL-21R has a distinct α chain, and contains six tyrosine residues in the cytoplasmic domain (3,5). This specific IL-21R structure differentiates IL-21R from IL-2R. IL-21 exerts its effect on a broad range of cell types. Increasing evidence shows that IL-21 potently regulates innate and adaptive immune response (68). Furthermore, the role of IL-21 in angiogenesis has also been studied (9,10). In the present review, the recent advances regarding the role of IL-21 in immune cells and angiogenesis are discussed.

Function of IL-21 on immune cells

Although IL-21 is not required for CD4+ T-cell development, it contributes to the functional differentiation of several subsets (11,12), such as T helper 2 (Th2) cells (13,14), Th17 (15,16) and follicular helper T (Tfh) cells (17,18). Th17 and Tfh cells can be generated in the absence of IL-21/IL-21R (16), indicating an IL-21-independent pathway for their development. IL-21 is produced by the Th17 cells, and transforming growth factor-β (TGF-β) and IL-6 can activate Th17 cells even in the absence of IL-21 (19,20). IL-21 regulates the transcription factors B-cell lymphoma 6 (BCL-6) and MAF, which are important to the transcriptional programme of the Tfh cells (21,22). IL-6 can induce Tfh-cell differentiation via its induction of IL-21 production. The number of Treg cells is increased in IL-21- and IL-6-knockout mice, and TGF-β signaling enhances the generation of Treg cells in the absence of either IL-21 or IL-6 (23,24). Thus, IL-21 appears to have a complementary role in regulating CD4+ T-cell differentiation.

B-cell expression of IL-21R notably exceeds that of T cells. A large number of studies confirm that IL-21 involved in the regulation of both B cell proliferation and maturation. IL-21 can stimulate B cells proliferation and differentiation in the context of a co-stimulatory T-cell signal. IL-21-mediated human B-cell differentiation requires signal transducer and activator of transcription 3 (STAT3), and cannot be compensated by alternative signaling pathways (25). The effect of IL-21 can be augmented by IL-2 or IL-10, and IL-21 induces IL-10 in human B cells and interacts with TGF-β (26,27). In particular, IL-21 promotes B cells differentiation to Ig-producing plasma through its induction of B lymphocyte-induced maturation protein-1 (28), which is a transcription factor critical for plasma cell formation. Notably, IL-21 also induces B cell apoptosis either in the absence of a T-cell signal or in the activation of a Toll-like receptor signal (29). The pro-apoptotic activity of IL-21 results from the induction of BCL-2, which is a pro-apoptotic protein.

IL-21 has broad actions on T and B cells, but its innate immunity is poorly understood. IL-21 has a potent inhibitory effect on granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced dendritic cells (DCs) (30). IL-21 induces apoptosis of conventional DCs (cDCs) via STAT3 and inhibiting Bim, and this effect is prevented by GM-CSF, which partially opposes the biological action by these cytokines. Furthermore, the number of STAT3 sites was reduced in the presence of GM-CSF when DCs were treated with IL-21, and GM-CSF primarily activates STAT5 instead of STAT3 and inhibits Bim (31). These findings suggest that IL-21-induced STAT3-dependent apoptosis of DCs provides a mechanism for alleviating the immune response, and IL-21 has a cross-negative regulation with GM-CSF.

Signaling by IL-21

IL-21 regulates the innate and adaptive immune responses via heterodimers of the IL-21R and the common cytokine receptor γc1. IL-21 signals via the Janus kinase (JAK)-STAT signaling pathway (25,26), the mitogen-activated protein kinase signaling pathway and the phosphoinositide 3-kinase-AKT signaling pathway (2). Of these, the JAK-STAT pathway has been the most extensively studied. In T cells, IL-21 activates STAT3 more than STAT1 and STAT5. STAT1 and STAT3 have partially opposing roles in IL-21 signaling. RNA-sequence analysis showed that STAT1 and STAT3 are critical for IL-21-mediated gene regulation, including Tbx21 and interferon γ (32). Notably, IL-21-induced expression of suppressor of cytokine signaling 3 (Socs3) and Socs1 are decreased in Stat3−/− cells (33). SOCS3 and SOCS1 can negatively regulate STAT protein phosphorylation, and this may in part explain the opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells. In cDCs, IL-21 induces IL-1β production via a STAT3 dependent and nuclear factor-κB independent pathway. Furthermore, this processing in cDCs does not require caspase-1 or caspase-8, but depends on IL-21-mediated death (34). IL-21 can induce the expression of PR domain containing 1, with ZNF domain in multiple B lymphoma cell lines, and IL-21 induces STAT3 binding also bound interferon regulatory factor 4 (IRF4) in vivo (35,36), and Irf4−/− mice showed impaired IL-21 induced Tfh cells differentiation (37). These results reveal broad cooperative gene regulation by STAT3 and IRF4. In T cells, numerous target genes of IL-21 are regulated through basic leucine zipper transcription factor, ATF-like, JUN, IRF4 and STAT3 (37,38). Notably, these transcription factors are also potential targets through which IL-21 signaling may be regulated. Our recent study reported that IL-21 activated STAT3 in HUVECs exposed to ischemia conditions; however, there were no significant changes in STAT1, AKT1 or extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation at any time point following IL-21 treatment (9).

IL-21 and angiogenesis

It has been shown that IL-21R exists in endothelial cells (ECs), which is a key process in the formation of new blood vessels during angiogenesis. IL-21 treatment decreases EC proliferation and sprouting in vitro. Furthermore, in a tumor mouse model, IL-21 inhibited tumor angiogenesis in vivo and decreased angiogenesis vascular endothelial growth factor A and its receptors (10). Another study demonstrated conflicting results, in which genetic ablation of IL-21 in Apcmin/+ mice reduced STAT3 activation and diminished cytokines, including IL-6 and tumor necrosis factor-α, and decreased angiogenesis in the lesions (8).

In our recent study of a mouse model with surgical hindlimb ischemia (HLI), the IL-21R levels were higher in the EC-enriched fraction isolated from ischemic hindlimb muscle. Furthermore, HUVECs showed 10-fold IL-21R expression following hypoxia and serum starvation in vitro. IL-21 treatment increased cell viability, decreased cell apoptosis and augmented tube formation in HUVECs under ischemic conditions. Knockout IL-21R resulted in less perfusion recovery following HLI in vivo. In particular, the activated STAT3 pathway and increase in the BCL-2/BCL-2-associated X protein ratio were involved in the in vitro and in vivo experiments (9). These results suggest that the elevated IL-21R levels in EC in ischemia muscle are adaptive.

Potential therapeutic effect of IL-21

Numerous studies have shown that IL-21 has therapeutic effects in animal models of a wide range of diseases [including cancer (12), immunity-deficient disease (39), type 1 diabetes (40) and inflammatory bowel disease (41)] and various clinical trials are underway (42).

An investigation regarding the association between IL-21 levels and myocardial function following acute myocardial showed that plasma IL-21 concentration correlated significantly with left ventricular end-systolic volume index, and multivariate analysis suggested that IL-21 was an independent predictor of remodeling. Furthermore, IL-21 was also significantly associated with higher tissue inhibitor of metalloproteinases-4 (TIMP-4) concentrations and lower MMP-9 concentrations (43). A previous experiment demonstrated that IL-21R was expressed on cardiac fibroblasts (44), and whether IL-21 may directly stimulate MMP/TIMP release within the myocardium is unknown and merits further study.


IL-21 has been implicated in broad immunological processes since its discovery in 2000. IL-21 regulates at least 3 pathways (STAT3, ERK1/2 and AKT-1), which can either enhance cell survival or pro-apoptosis in different cell lines. IL-21 signaling pathways are complex due to their cooperation with other transcriptional factors. With the improvement of our understanding in IL-21 biology regarding each specific disease or pathological condition, IL-21 could be a new therapeutic target for immune relative disease.


The present study was partially supported by National Natural Science Foundation of China (grant no. 81300315)



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Yuan MJ and Yuan MJ: Advances of the interleukin‑21 signaling pathway in immunity and angiogenesis (Review). Biomed Rep 5: 3-6, 2016
Yuan, M., & Yuan, M. (2016). Advances of the interleukin‑21 signaling pathway in immunity and angiogenesis (Review). Biomedical Reports, 5, 3-6.
Yuan, M., Wang, T."Advances of the interleukin‑21 signaling pathway in immunity and angiogenesis (Review)". Biomedical Reports 5.1 (2016): 3-6.
Yuan, M., Wang, T."Advances of the interleukin‑21 signaling pathway in immunity and angiogenesis (Review)". Biomedical Reports 5, no. 1 (2016): 3-6.