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Review

Mechanistic roles of interleukin‑18 in colonic immunity across infection, inflammatory bowel disease, and colorectal cancer (Review)

  • Authors:
    • Jingwen Zhang
    • Lili Bao
    • Xia Li
    • Jiaxi Li
    • Jiaxian Cui
    • Lu Qiao
    • Xiaoxia He
    • Mingyu Zhang
    • Jingkun Lu
    • Xuan Zhang
    • Jing Dong
    • Gesi Tao
    • Tuya Bai
    • Yun Peng Tian
    • Pengwei Zhao
    • Ya Tuo
  • View Affiliations / Copyright

    Affiliations: Department of Clinical Laboratory, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010059, P.R. China, Laboratory of Microbiology and Immunology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010059, P.R. China, School of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region 010059, P.R. China
  • Article Number: 163
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    Published online on: April 17, 2026
       https://doi.org/10.3892/ijmm.2026.5834
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Abstract

The colon, functioning as a central organ for digestion, absorption, and immune defense in the human body, depends on intricate interactions among the epithelial barrier, immune cells, and gut microbiota to sustain mucosal homeostasis. Dysregulation within cytokine networks constitutes a key pathogenic driver of colonic disorders, including inflammation, infection, and tumorigenesis. Interleukin (IL)‑18, a pivotal cytokine in colonic immune modulation, exhibits dual roles in maintaining homeostasis and mediating pathology: IL‑18 orchestrates immune responses through both inflammasome‑dependent and ‑independent mechanisms, exerting bidirectional influences on colonic pathogen eradication and inflammatory exacerbation. The coordinated actions of IL‑18 and IL‑22, mediated via epithelium‑specific receptor signaling, primarily govern colonic barrier restoration and antimicrobial defense, undergoing functional transitions throughout disease progression. The present review systematically elucidates the molecular characteristics of IL‑18 and its mechanistic functions in colonic pathogen defense and disorders such as inflammatory bowel disease and colorectal cancer, following the logical framework of molecular mechanisms, physiological roles, pathological regulation, and interactive networks. The synergistic and antagonistic interactions among IL‑18 and IL‑22 are analyzed, and their clinical translational potential is explored, providing a theoretical basis for precision intervention in colonic pathologies. Based on clinical and mechanistic studies, this review systematically integrates existing experimental evidence to provide a theoretical framework for understanding the complex roles of IL‑18 in colonic immunity. Although targeted intervention of IL‑18 holds promise in animal models, its clinical translation warrants further validation through human studies, given its context‑dependent functions and potential risks.
View Figures

Figure 1

Schematic diagram of IL-18
production, signaling pathways, and synergistic networks with
IL-22. Illustration of the classical molecular mechanisms
underlying IL-18 maturation and signal transduction in the context
of pathogen infection (such as bacterial infection). Experimental
evidence is primarily derived from cell culture studies and murine
models. i) The process begins with a priming signal: LPS
upregulates the expression of NLRP3 and pro-IL-18 via
TLR4-dependent NF-κB signaling. Subsequent activation signals,
including ATP acting through the P2X7 receptor, K+
efflux via the TWIK2 channel, mitochondrial dysfunction-induced ROS
production and Ca2+ flux, as well as ER stress,
collectively trigger NLRP3 inflammasome assembly and caspase-1
activation. Activated caspase-1 cleaves pro-IL-18 into mature
IL-18, which is released extracellularly. Secreted IL-18 then binds
to the heterodimeric IL-18Rα/β receptor complex on immune cells
(such as Th1 cells and NK cells), recruiting MyD88 and activating
transcription factors such as NF-κB and AP-1, thereby inducing the
production of pro-inflammatory cytokines including IFN-γ and TNF-α.
IL-18BP functions as a high-affinity soluble inhibitor that
neutralizes free IL-18, forming a negative feedback mechanism that
limits excessive inflammation. Furthermore, IL-18 and IL-22
establish a key synergistic regulatory axis: In intestinal
infections (such as AIEC, Toxoplasma gondii infection),
IL-18 promotes IL-22 production by ILC3s via the HIF-1α pathway,
while IL-22 further induces pro-IL-18 synthesis in epithelial
cells, forming a positive feedback loop that enhances antimicrobial
peptide secretion and mucosal barrier function. ii) Pathway status:
The following steps are well established: a) TLR4/NF-κB-dependent
upregulation of NLRP3 and pro-IL-18 expression (priming signal); b)
NLRP3 inflammasome assembly and caspase-1 activation triggered by
ATP, mtROS, and K+ efflux; c) caspase-1-mediated
cleavage of pro-IL-18 into mature IL-18; d) IL-18 binding to
IL-18Ra/β and subsequent activation of downstream MyD88/NF-κB/AP-1
signaling; e) IL-18BP-mediated negative feedback regulation.
However, the specific molecular mechanisms by which ER-mitochondria
crosstalk, CLIC-dependent Cl− efflux, and mtDNA
oxidation finely regulate NLRP3 activation remain to be fully
elucidated. Furthermore, the extent to which these regulatory nodes
contribute to tissue-specific or context-dependent IL-18 responses
requires further investigation. AIEC, adherent-invasive Escherichia
coli; ATP, adenosine triphosphate; TWIK2, twopore domain weak
inwardly rectifying K+ channel 2; TLR4, Tolllike
receptor 4; LPS, lipopolysaccharide; SCFAs, shortchain fatty acids;
IL22, interleukin22; ROS, reactive oxygen species; NLRP3, NODlike
receptor family pyrin domaincontaining protein 3; NLRP6, NODlike
receptor family pyrin domaincontaining protein 6; ASC,
apoptosis-associated speck-like protein; NFκB, nuclear factorκB;
IL-18, interleukin18; AMP, antimicrobial peptide; pro-IL-18,
pro-interleukin-18; ER, endoplasmic reticulum; IL18Rα,
interleukin18 receptor α; IL18Rβ, interleukin18 receptor β; MyD88,
myeloid differentiation primary response 88; TIR,
Toll/interleukin-1 receptor; TRAM, TRIF-related adaptor molecule;
IRAK1, interleukin-1 receptor-associated kinases 1; IRAK4,
interleukin-1 receptor-associated kinases 4; IKKs, inhibitory kappa
B kinases; AP-1, activator protein-1; HIF-1α, hypoxia-inducible
factor 1α; IFN-γ, interferonγ; Th1, T-helper 1; IL-18BP, IL-18
binding protein; ILC3, type 3 innate lymphoid cell; IL-1β,
interleukin-1β; NO, nitric oxide; caspase-1, cysteine-dependent
aspartate-directed protease-1; caspase-11, cysteine-dependent
aspartate-directed protease-11.

Figure 2

IL-18 in colonic pathogen defense and
disease. i) Summary of the context-dependent functions of IL-18 in
the colon, covering intestinal infections and inflammatory diseases
(IBD and colorectal cancer). The mechanisms summarized here are
supported by evidence from animal models, human clinical samples,
and in vitro immune cell studies. (A) Host defense against
pathogens: Against extracellular pathogens (such as Escherichia
coli and Pseudomonas aeruginosa), IL-18 enhances IFN-γ
production, IgM responses, and neutrophil activity, primarily
demonstrated in murine infection models. Against intestinal
helminths (such as Trichinella spiralis and
Trichuris), IL-18 exhibits bidirectional regulatory effects
by modulating Th2 cytokines and mucosal mast cell activation.
Against intracellular pathogens (such as Mycobacterium and
Salmonella), IL-18 synergizes with IL-12 to drive Th1
immunity. (B) Eosinophil-associated gastrointestinal diseases:
IL-18 activates B cells and iNKT cells, promoting IgE production
and eosinophil recruitment. (C) UC: Mitochondrial stress activates
the NLRP3 inflammasome (ASC and caspase-1), promoting the cleavage
of pro-IL-18 into mature IL-18; IL-18 subsequently drives Th1-type
immune responses (production of IFN-γ and TNF-α), amplifying
intestinal inflammation. (D) CD: IL-18 synergizes with IL-12 to
induce IFN-γ production by Th1 cells, amplifying intestinal
inflammation. (E) CRC: IL-18 enhances antitumor immunity primarily
by activating NK cell cytotoxicity. ii) Pathway status: The roles
of IL-18 in pathogen defense (such as IFN-γ induction, neutrophil
activation) and in disease contexts (such as synergy with IL-12 in
CD, amplification of Th1 inflammation in UC, NK cell activation in
CRC) are supported by experimental evidence. However, the molecular
mechanisms governing the context-dependent switch between its
protective and pathogenic functions, particularly the integration
of signals from different cellular sources (epithelial cells vs.
immune cells) and disease stages, remain to be fully elucidated.
IL-3, interleukin-3; IL-2, interleukin-2; IL-12, interleukin-12;
IL-18, interleukin-18; NK cell, natural killer cell; IFN-γ,
interferonγ; iNOS, inducible NO synthase; NO, nitric oxide; iNKT
cell, invariant natural killer T cell; APC, antigen-presenting
cell; VDAC1, voltage-dependent anion channel 1; mROS, mitochondrial
reactive oxygen species; mtDNA, mitochondrial DNA; OX-mtDNA,
oxidized mitochondrial DNA; NLRP3, NODlike receptor family pyrin
domaincontaining protein 3; ASC, apoptosis-associated speck-like
protein; caspase-1, cysteine-dependent aspartate-directed
protease-1; pro-IL-18, pro-interleukin-18; Th1, T-helper 1; TNFα,
tumor necrosis factorα; IL-18Rα, interleukin18 receptor α; IL-12R,
interleukin-12 receptor; STAT4, signal transducer and activator of
transcription 4; NF-κB, nuclear factorκB; IBD, inflammatory bowel
disease; UC, ulcerative colitis; CRC, colorectal cancer; CD,
Crohn's disease.

Figure 3

Schematic diagram of the
time-dependent functional switch of IL-18 and IL-22 in colitis. i)
Illustration of the stage-dependent roles of IL-18 in the context
of inflammatory bowel disease (experimental colitis), based
primarily on findings from DSS-induced murine colitis models. (A)
Early inflammatory phase: IL-18 activates the IL-22/STAT3 signaling
pathway, promoting goblet cell maturation and mucus secretion,
enhancing Paneth cell antimicrobial peptide release, and
stimulating Lgr5+ intestinal stem cell proliferation.
These processes collectively strengthen epithelial barrier
integrity and facilitate tissue repair. (B) Late inflammatory
phase: IL-18 strongly induces the expression of IL-22BP, which acts
as a high-affinity decoy receptor that neutralizes IL-22. This
leads to suppression of the STAT3 signaling pathway, resulting in
impaired goblet cell function, reduced mucus production, decreased
Paneth cell antimicrobial activity, and impaired intestinal stem
cell renewal, thereby exacerbating epithelial damage and
inflammation. ii) Pathway status: The dual role of IL-18 in
colitis, promoting epithelial repair in the early phase via
IL-22/STAT3 activation and driving barrier disruption in the late
phase via IL-22BP induction, is supported by experimental animal
studies. However, the molecular mechanisms triggering this
functional switch, the integration of additional microenvironmental
signals, and the translational relevance to human IBD remain to be
elucidated. IL-18, interleukin-18; IL-22, interleukin-22; IL-22BP,
interleukin-22 binding protein; ILC3, group 3 innate lymphoid cell;
NKT, natural killer T cell; STAT3, signal transducer and activator
of transcription 3; TA, transit-amplifying cell; Th17 cell,
T-helper 17 cell; IBD, inflammatory bowel disease; DSS, dextran
sulfate sodium.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang J, Bao L, Li X, Li J, Cui J, Qiao L, He X, Zhang M, Lu J, Zhang X, Zhang X, et al: Mechanistic roles of interleukin‑18 in colonic immunity across infection, inflammatory bowel disease, and colorectal cancer (Review). Int J Mol Med 57: 163, 2026.
APA
Zhang, J., Bao, L., Li, X., Li, J., Cui, J., Qiao, L. ... Tuo, Y. (2026). Mechanistic roles of interleukin‑18 in colonic immunity across infection, inflammatory bowel disease, and colorectal cancer (Review). International Journal of Molecular Medicine, 57, 163. https://doi.org/10.3892/ijmm.2026.5834
MLA
Zhang, J., Bao, L., Li, X., Li, J., Cui, J., Qiao, L., He, X., Zhang, M., Lu, J., Zhang, X., Dong, J., Tao, G., Bai, T., Tian, Y. P., Zhao, P., Tuo, Y."Mechanistic roles of interleukin‑18 in colonic immunity across infection, inflammatory bowel disease, and colorectal cancer (Review)". International Journal of Molecular Medicine 57.6 (2026): 163.
Chicago
Zhang, J., Bao, L., Li, X., Li, J., Cui, J., Qiao, L., He, X., Zhang, M., Lu, J., Zhang, X., Dong, J., Tao, G., Bai, T., Tian, Y. P., Zhao, P., Tuo, Y."Mechanistic roles of interleukin‑18 in colonic immunity across infection, inflammatory bowel disease, and colorectal cancer (Review)". International Journal of Molecular Medicine 57, no. 6 (2026): 163. https://doi.org/10.3892/ijmm.2026.5834
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang J, Bao L, Li X, Li J, Cui J, Qiao L, He X, Zhang M, Lu J, Zhang X, Zhang X, et al: Mechanistic roles of interleukin‑18 in colonic immunity across infection, inflammatory bowel disease, and colorectal cancer (Review). Int J Mol Med 57: 163, 2026.
APA
Zhang, J., Bao, L., Li, X., Li, J., Cui, J., Qiao, L. ... Tuo, Y. (2026). Mechanistic roles of interleukin‑18 in colonic immunity across infection, inflammatory bowel disease, and colorectal cancer (Review). International Journal of Molecular Medicine, 57, 163. https://doi.org/10.3892/ijmm.2026.5834
MLA
Zhang, J., Bao, L., Li, X., Li, J., Cui, J., Qiao, L., He, X., Zhang, M., Lu, J., Zhang, X., Dong, J., Tao, G., Bai, T., Tian, Y. P., Zhao, P., Tuo, Y."Mechanistic roles of interleukin‑18 in colonic immunity across infection, inflammatory bowel disease, and colorectal cancer (Review)". International Journal of Molecular Medicine 57.6 (2026): 163.
Chicago
Zhang, J., Bao, L., Li, X., Li, J., Cui, J., Qiao, L., He, X., Zhang, M., Lu, J., Zhang, X., Dong, J., Tao, G., Bai, T., Tian, Y. P., Zhao, P., Tuo, Y."Mechanistic roles of interleukin‑18 in colonic immunity across infection, inflammatory bowel disease, and colorectal cancer (Review)". International Journal of Molecular Medicine 57, no. 6 (2026): 163. https://doi.org/10.3892/ijmm.2026.5834
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