IL‐36<i>γ</i> and IL‐36Ra Reciprocally Regulate Colon Inflammation and Tumorigenesis by Modulating the Cell–Matrix Adhesion Network and Wnt Signaling

Yang, Wei; Dong, Hong-Peng; Wang, Peng; Xu, Zhigao; Xian, Jiahuan; Chen, Jiachen; Wu, Hai; Lou, Yang; Lin, Dandan; Zhong, Bo

doi:10.1002/advs.202103035

Cited by 16 publications

(12 citation statements)

References 64 publications

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“…In mice subjected to DSS colitis, IL-36α/γ and IL-38 gene expression are increased in the colon during the peak of colitis, whereas IL-36β, IL-36Ra, and IL-1R6 remained stable ( 38 , 39 ). Yang et al, recently reported that deficiency of the IL-1R6 agonist IL-36γ leads to hypo-responsiveness to DSS-induced colitis, whereas the IL-36Ra deficient mouse is hyper-responsive ( 40 ). These data are in line with our observations of amplified colitis in the IL-38 deficient mouse, and are consistent with IL-38 and IL-36Ra both inhibiting IL-1R6 signaling.…”

Section: Discussionmentioning

confidence: 99%

IL-38 Gene Deletion Worsens Murine Colitis

et al. 2022

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IL-38 is a recently discovered cytokine and member of the IL-1 Family. In the IL-1 Family, IL-38 is unique because the cytokine is primarily a B lymphocyte product and functions to suppress inflammation. Studies in humans with inflammatory bowel disease (IBD) suggest that IL-38 may be protective for ulcerative colitis or Crohn’s disease, and that IL-38 acts to maintain homeostasis in the intestinal tract. Here we investigated the role of endogenous IL-38 in experimental colitis in mice deficient in IL-38 by deletion of exons 1-4 in C57 BL/6 mice. Compared to WT mice, IL-38 deficient mice subjected to dextran sulfate sodium (DSS) showed greater severity of disease, more weight loss, increased intestinal permeability, and a worse histological phenotype including increased neutrophil influx in the colon. Mice lacking IL-38 exhibited elevated colonic Nlrp3 mRNA and protein levels, increased caspase-1 activation, and the concomitant increased processing of IL-1β precursor into active IL-1β. Expression of IL-1α, an exacerbator of IBD, was also upregulated. Colonic myleloperoxidase protein and Il17a, and Il17f mRNA levels were higher in the IL-38 deficient mice. Daily treatment of IL-38 deficient mice with an NLRP3 inhibitor attenuated diarrhea and weight loss during the recovery phase. These data implicate endogenous IL-38 as an anti-inflammatory cytokine that reduces DSS colitis severity. We propose that a relative deficiency of IL-38 contributes to IBD by disinhibition of the NLRP3 inflammasome.

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Section: Discussionmentioning

confidence: 99%

IL-38 Gene Deletion Worsens Murine Colitis

et al. 2022

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“…Similarly, 4T1-IL-36γ-injected CB57/BL6 mice exhibited increased Th1 anti-tumorigenic responses and decreased lung metastasis, indicating its anti-tumor effects [ 24 ]. However, increased levels of IL-36γ have been identified in non-small cell lung cancer and colon cancer tissues [ 26 , 42 ]. In addition, IL-36γ exerts pro-tumorigenic effects resulting from increased proliferation, migration, and invasion of colon cancer cells [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…According to a recent study, IL-36γ exerts a critical function in the progression of colon cancer [ 26 ]. Knockout of IL-36γ led to decreased tumor incidence in various mice models of colon cancer, such as AOM/DSS, AOM/Vil-Cre, Trp53fl/fl, and ApcMin/+ [ 26 ]. Proliferation of CRC cell lines was also increased by IL-36R-mediated IL-36γ signaling [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, IL-36γ significantly increased colorectal cancer (CRC) cell proliferation [ 25 ]. In addition, the knockout (KO) of IL-36γ reduced tumors in the small intestine of mice, indicating a pro-tumorigenic role of IL-36γ in the progression of colon cancer [ 26 ]. Although the dual function of IL-36γ in cancers has been demonstrated in these studies, its underlying molecular mechanism in the development of breast cancer has not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Interleukin-36γ/IL-36R Signaling Axis by PIN1 in Epithelial Cell Transformation and Breast Tumorigenesis

Poudel

Bhattarai

Shrestha

et al. 2022

Cancers

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Given the increasing recognition of the relationship between IL-1 cytokines, inflammation, and cancer, the significance of distinct members of the IL-1 cytokine family in the etiology of cancer has been widely researched. In the present study, we investigated the underlying mechanism of the IL-36γ/IL-36R axis during breast cancer progression, which has not yet been elucidated. Initially, we determined the effects of IL-36γ on the proliferation and epithelial cell transformation of JB6 Cl41 mouse epidermal and MCF7 human breast cancer cells using BrdU incorporation and anchorage-independent growth assays. We found that treatment with IL-36γ increased the proliferation and colony formation of JB6 Cl41 and MCF7 cells. Analysis of the mechanism underlying the neoplastic cell transformation revealed that IL-36γ induced IL-36R-mediated phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun, resulting in increased c-Fos, c-Jun, and AP-1 activities in JB6 Cl41 and MCF7 cells. Furthermore, the IL-36γ-induced tumorigenic capacity of MCF7 cells was considerably enhanced by PIN1, following MEK/ERK and JNK/c-Jun signaling. Interestingly, blocking PIN1 activity using juglone suppressed the IL-36γ-induced increase in the anchorage-independent growth of 4T1 metastatic mouse breast cancer cells. Finally, in a syngeneic mouse model, IL-36γ-induced tumor growth in the breast mammary gland was significantly inhibited following PIN1 knockout.

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“…However, several reports have proposed the opposite view that IL-36γ promotes the development of CRC ( 32 , 87 , 88 ). In the intestinal cancer model, injection of anti-IL-36γ significantly inhibits the tumorigenesis and tumor development in the colon and the small intestine along with the expression of cell-matrix adhesion molecules and Wnt downstream genes in the colon tumors ( 87 ). Therefore, IL-36γ may contribute to tumorigenesis by indirectly regulating Wnt signaling through inducing the expression of cell-matrix adhesion molecules ( 87 ).…”

Section: Role Of Il-36 In Colorectal Cancermentioning

confidence: 99%

New insights on IL‑36 in intestinal inflammation and colorectal cancer (Review)

Jiang

Wang

et al. 2023

Exp Ther Med

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Interleukin (IL)-36 is a member of the IL-1 superfamily, which includes three receptor agonists and one antagonist and exhibits a familial feature of inflammatory regulation. Distributed among various tissues, such as the skin, lung, gut and joints, the mechanism of IL-36 has been most completely investigated in the skin and has been used in clinical treatment of generalized pustular psoriasis. Meanwhile, the role of IL-36 in the intestine has also been under scrutiny and has been shown to be involved in the regulation of various intestinal diseases. Inflammatory bowel disease and colorectal cancer are the most predominant inflammatory and neoplastic diseases of the intestine, and multiple studies have identified a complex role for IL-36 in both of them. Indeed, inhibiting IL-36 signaling is currently regarded as a promising therapeutic approach. Therefore, the present review briefly describes the composition and expression of IL-36 and focuses on the role of IL-36 in intestinal inflammation and colorectal cancer. The targeted therapies that are currently being developed for the IL-36 receptor are also discussed.

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IL‐36γ and IL‐36Ra Reciprocally Regulate Colon Inflammation and Tumorigenesis by Modulating the Cell–Matrix Adhesion Network and Wnt Signaling

Cited by 16 publications

References 64 publications

IL-38 Gene Deletion Worsens Murine Colitis

IL-38 Gene Deletion Worsens Murine Colitis

Regulation of Interleukin-36γ/IL-36R Signaling Axis by PIN1 in Epithelial Cell Transformation and Breast Tumorigenesis

New insights on IL‑36 in intestinal inflammation and colorectal cancer (Review)

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