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Roles of interleukins in spasmolytic polypeptide‑expressing metaplasia (Review)

  • Authors:
    • Jiale Ma
    • Tiancheng Zhan
    • Xinyuan Zhang
    • Wang Gao
    • Shuangmei Zhao
    • Huizhen Li
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    Affiliations: Department of Gastroenterology, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300250, P.R China, Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, P.R. China
    Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 17
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    Published online on: December 3, 2025
       https://doi.org/10.3892/ijo.2025.5830
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Abstract

Gastric cancer (GC) is a major global health burden, ranking fifth in incidence and third in cancer‑related mortality. By 2040, there are expected to be ~1.8 million new cases and 1.3 million fatalities associated with GC. Spasmolytic polypeptide‑expressing metaplasia (SPEM) is a central component of gastric precancerous lesions, which remodels the gastric mucosa in response to injury through a lineage of mucus‑secreting cells. Interleukins (ILs) are the communication means for innate and adaptive immune cells as well as non‑immune cells and tissues. Their complex network regulation contributes to the development of SPEM and is a key driver in the transformation of SPEM to GC. The present review systematically described the IL‑related mechanisms underlying the formation and progression of SPEM and categorizes the roles of different ILs by family. In addition, the molecular association between IL dynamics and SPEM following Helicobacter pylori infection is explored, and various SPEM experimental model characteristics and IL‑based therapeutic strategy advances and limitations are discussed. The clinical translation of IL‑targeted therapies is limited, but the development of therapies that target pathogenesis specifically and the enhancement of IL therapy combinations with other therapeutic options may improve efficacy and reduce side effects. Increased understanding of the causes of SPEM and the mechanisms underlying GC may open up new avenues for early detection and targeted therapy.
View Figures

Figure 1

IL family surface receptors and
intracellular signaling. The IL-2 interleukin family receptors for
IL-2, IL-15, IL-7, IL-9, IL-21 and IL-4 share a common γc subunit.
IL-2 and IL-15 also share IL-2Rβ. All γc cytokines activate JAK1
and JAK3. They phosphorylate various STAT proteins downstream by
activating the JAK/STAT signaling pathway. The IL-2 receptor has
forms with low, intermediate and high affinity and activates
JAK-STAT, PI3K and MAPK signaling pathways upon its engagement in
the specific receptor complexes. There are three forms of IL-4
receptors involving the IL-4Rα subunit, γc chain, IL-13Rα1 subunit
and the IL-2Rα subunit, which activate the PI3K and MAPK pathways.
IL-4 activates intracellular pathways to produce phosphorylated
STAT6, ERK and AKT. IL-6 has classical and trans-signaling
properties and activates multiple intracellular pathways, including
JAK1-STAT3, RAS-MAPK and PI3K-AKT. IL-1 family receptors are
heterodimers consisting of ligand-sensing and signaling monomers.
Cellular activation by stimulation of the polymerization of the
IRAK4-MyD88 complex leads to the recruitment of IRAK1/2, further
recruitment of TRAF6 and activation of MAPK/NIK, and finally
activation of the IKK complex, NF-κB, AP-1 and IRFs. IL-33/ST2
activates NF-κB, PI3K/AKT, MAPKs and ERK1/2. The six members of the
IL-17 family form homodimers and heterodimers that recruit the
ubiquitin ligase Act1 to the SEFIR structural domain, triggering
the downstream TRAF6-TAK1-NF-κB pathway, as well as activating the
C/EBP and MAPK pathways. IL, interleukin; IRFs, interferon
regulatory factors; γc, γ-chain; IRAK4, IL-1 receptor-associated
kinase; MyD88, myeloid differentiation primary response 88; TRAF6,
tumor necrosis factor receptor-associated factor 6; NIK,
NF-κB-inducing kinase; AP-1, activator protein 1; SEFIR, similar
expression to fibroblast growth factor genes/IL-17 receptors; TAK1,
TGF-β-activated kinase 1; C/EBP, CCAAT/enhancer-binding
protein.

Figure 2

ILs in the progression of SPEM. IL-18
promotes the Th1 response to induce chronic persistent inflammation
and mediates IFN-γ to generate gastritis. IL-2 induces TNF-α and
IFN-γ to promote SPEM, and high IL-2 inhibits gastric
acid-associated chronic inflammation. IL-10 inhibits gastric
tissues from entering the SPEM state. IL-1β inhibits gastric acid
secretion and induces gastric mucosal atrophy that directly
promotes SPEM development, stimulates proliferation of gastric
epithelial cells and promotes Helicobacter pylori damage to
the parietal cells, leading to gastric carcinogenesis. IL-6
triggers alterations in the SPEM spectrum, and disruption of the
pathway may favor the development of gastric adenomas. IL-11
triggers the progression of spontaneous atrophic gastritis to
locally advanced epithelial hyperplasia but does not initiate
cancer. The chronic inflammatory state caused by IL-8 may drive
SPEM gastric cancer early stage and pre-cancer progression. IL-33
activates the ST2 signaling axis to drive a Th2-type immune
response and facilitates IL-13-induced transdifferentiation of
chief cells into SPEM cells. IL-13 also promotes the maturation and
stabilization of SPEM. IL-4 suppresses inflammation by decreasing
IFN-γ. By reducing immune cells' secretion of IL-17A, IL-27
considerably lessens the severity of gastritis and SPEM. At the
same time, it signals directly to gastric epithelial cells to slow
the development of gastric metaplasia. IL-17A directly promotes the
development of chronic atrophic gastritis and SPEM and promotes
cancer progression. IL, interleukin; SPEM, spasmolytic
polypeptide-expressing metaplasia.

Figure 3

IL-33, IL-25, IL-13 and IL-17 are
associated with the onset and progression of gastric epithelial
metaplasia as SPEM. Epithelial injury and parietal cell apoptosis
lead to the release of IL-33, which causes macrophage polarization
toward M2. IL-25 released by tuft cells along with IL-33 also
contributes to the potential induction of ILC2 activation and
proliferation. M2 macrophages and eosinophils in turn produce IL-13
and more IL-33. B cells, Th2 cells and mast cells also produce
IL-13. The development of SPEM is aided by the downstream release
of IL-13 and IL-17, which are produced by various T cells and NK
cells. IL, interleukin; SPEM, spasmolytic polypeptide-expressing
metaplasia; NK, natural killer; Th, T helper cell.

Figure 4

IL-33/ILC2s/IL-13 axis regulates the
development of spasmolytic polypeptide-expressing metaplasia. When
mucosal damage or parietal cell loss occurs, IL-33 is released and
interacts with the IL-33 receptor (ST2) on type II innate
lymphocytes (ILC2s). IL-13 signaling downstream of IL-33 promotes
SPEM formation and the selective activation of macrophages to M2.
Activated macrophages generate IL-33, which may further increase
IL-13 release and aid in chief cell transdifferentiation into SPEM
cells. IL, interleukin; SPEM, spasmolytic polypeptide-expressing
metaplasia.

Figure 5

Dynamics of H. pylori
infection and ILs. After infection, IL-8 expression activates and
recruits neutrophils to the gastric mucosa to establish an innate
immune response against H. pylori infection. Dendritic cell
secretion produces IL-12 and IL-23 to activate Th1 and Th17 cells,
respectively and Th1 cells release IL-2 and IFN-γ, which stimulate
B-cell differentiation and anti-H. pylori IgG secretion.
Synergistic IL-17A is increased by IL-23, and when combined with
IL-22, it causes IL-8 secretion and intensifies the inflammatory
response. The virulence factor CagA triggers upregulation of IL-8
or IL-32. Treg cells are activated by IL-18 and IL-1β to modulate
the immune response and lead to persistent infection. Infection
leading to massive production of IL-1β, IL-6 and IL-11 may
exacerbate mucosal damage, inhibit gastric acid secretion and
promote chronic inflammation. DC-produced IL-10 and TGF-β inhibit
host immune response through Treg differentiation. Below right is
the structure of H. pylori. IL, interleukin; SPEM,
spasmolytic polypeptide-expressing metaplasia; Th, T helper cell;
Treg, T regulatory cell; CagA, Cytotoxin-associated antigen A; DC,
dendritic cell; Helicobacter pylori, H. pylori; VacA,
vacuolating cytotoxin A.
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Copy and paste a formatted citation
Spandidos Publications style
Ma J, Zhan T, Zhang X, Gao W, Zhao S and Li H: Roles of interleukins in spasmolytic polypeptide‑expressing metaplasia (Review). Int J Oncol 68: 17, 2026.
APA
Ma, J., Zhan, T., Zhang, X., Gao, W., Zhao, S., & Li, H. (2026). Roles of interleukins in spasmolytic polypeptide‑expressing metaplasia (Review). International Journal of Oncology, 68, 17. https://doi.org/10.3892/ijo.2025.5830
MLA
Ma, J., Zhan, T., Zhang, X., Gao, W., Zhao, S., Li, H."Roles of interleukins in spasmolytic polypeptide‑expressing metaplasia (Review)". International Journal of Oncology 68.2 (2026): 17.
Chicago
Ma, J., Zhan, T., Zhang, X., Gao, W., Zhao, S., Li, H."Roles of interleukins in spasmolytic polypeptide‑expressing metaplasia (Review)". International Journal of Oncology 68, no. 2 (2026): 17. https://doi.org/10.3892/ijo.2025.5830
Copy and paste a formatted citation
x
Spandidos Publications style
Ma J, Zhan T, Zhang X, Gao W, Zhao S and Li H: Roles of interleukins in spasmolytic polypeptide‑expressing metaplasia (Review). Int J Oncol 68: 17, 2026.
APA
Ma, J., Zhan, T., Zhang, X., Gao, W., Zhao, S., & Li, H. (2026). Roles of interleukins in spasmolytic polypeptide‑expressing metaplasia (Review). International Journal of Oncology, 68, 17. https://doi.org/10.3892/ijo.2025.5830
MLA
Ma, J., Zhan, T., Zhang, X., Gao, W., Zhao, S., Li, H."Roles of interleukins in spasmolytic polypeptide‑expressing metaplasia (Review)". International Journal of Oncology 68.2 (2026): 17.
Chicago
Ma, J., Zhan, T., Zhang, X., Gao, W., Zhao, S., Li, H."Roles of interleukins in spasmolytic polypeptide‑expressing metaplasia (Review)". International Journal of Oncology 68, no. 2 (2026): 17. https://doi.org/10.3892/ijo.2025.5830
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