Interleukin-33 regulates intestinal inflammation by modulating macrophages in inflammatory bowel disease

Seo, Dong Hyuk; Che, Xiumei; Kwak, Min Seob; Kim, Soochan; Kim, Jae Hyun; Woo, Hyun Jun; Kim, Da Hye; Kim, Tae Il; Kim, Won Ho; Kim, Seung Won; Cheon, Jae Hee

doi:10.1038/s41598-017-00840-2

Cited by 90 publications

(91 citation statements)

References 59 publications

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“…This conferred protection to recipient mice, in which there was a significant decrease in intestinal disease and inflammatory markers [131]. A similar finding was found in which peritoneal injection of IL-33 in experimental colitis induced M2 macrophage polarization, which subsequently resulted in goblet cell differentiation and attenuated inflammation [132]. Taken together, these studies suggest IL-33 signaling may be protective in experimental colitis via induction of type 2 immune responses and induction of immune cells involved in mitigating intestinal inflammation.…”

Section: Il-33/st2 Signaling Axis In Inflammatory Bowel Diseasementioning

confidence: 66%

“…In other studies, IL-33 was protective in colitis by inducing polarization of macrophages to M2 macrophages, which are typically associated with T H 2 cytokines and promote resolution of inflammation [131, 132]. In one study, these M2 macrophages, which they termed alternatively activated macrophages, were isolated from IL-33-treated mice and transferred to mice with TNBS-induced colitis [131].…”

Section: Il-33/st2 Signaling Axis In Inflammatory Bowel Diseasementioning

confidence: 99%

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IL-33 and the intestine: The good, the bad, and the inflammatory

et al. 2017

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Interleukin-33 (IL-33) is a member of the IL-1 cytokine family that has been widely studied since its discovery in 2005 for its dichotomous functions in homeostasis and inflammation. IL-33, along with its receptor suppression of tumorigenicity 2 (ST2), has been shown to modulate both the innate and adaptive immune system. Originally, the IL-33/ST2 signaling axis was studied in the context of inducing type 2 immune responses with the expression of ST2 by T helper 2 (TH2) cells. However, the role of IL-33 is not limited to TH2 responses. Rather, IL-33 is a potent activator of TH1 cells, group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, and CD8+ T cells. The intestine is uniquely important in this discussion, as the intestinal epithelium is distinctively positioned to interact with both pathogens and the immune cells housed in the mucosa. In the intestine, IL-33 is expressed by the pericryptal fibroblasts and its expression is increased particularly in disease states. Moreover, IL-33/ST2 signaling aberrancy is implicated in the pathogenesis of inflammatory bowel disease (IBD). Accordingly, for this review, we will focus on the role of IL-33 in the regulation of intestinal immunity, involvement in intestinal disease, and implication in potential therapeutics.

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Section: Il-33/st2 Signaling Axis In Inflammatory Bowel Diseasementioning

confidence: 66%

Section: Il-33/st2 Signaling Axis In Inflammatory Bowel Diseasementioning

confidence: 99%

IL-33 and the intestine: The good, the bad, and the inflammatory

et al. 2017

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“…For example, high levels of IL‐6 and TNF‐R2 were reported to be associated with refractoriness to IFX in CD through a TNF‐α‐independent pathway . IL‐33 or IL‐12B has been shown to be related with modulation and activity of the disease . These cytokines might be associated with IFX resistance in IBD patients through an alternative pathway, without TNF‐α.…”

Section: Discussionmentioning

confidence: 99%

“…35 IL-33 or IL-12B has been shown to be related with modulation and activity of the disease. 36,37 These cytokines might be associated with IFX resistance in IBD patients through an alternative pathway, without TNF-α. In our multivariate analysis, rs9144 located in the RAB38 gene was found to be associated with LOR.…”

Section: Discussionmentioning

confidence: 99%

ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases

Jung

Choi

Kim

et al. 2019

J of Gastro and Hepatol

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Background and Aim Infliximab has been widely prescribed for treating inflammatory bowel disease (IBD). However, the response rates to infliximab differ among patients. Therefore, we aimed to identify the genetic and clinical markers that predict infliximab response. Methods A total of 139 Korean patients with IBD who received infliximab were classified according to infliximab response as follows: (i) primary response vs nonresponse and (ii) sustained response vs loss of response. We performed an association study using whole‐exome sequencing data to identify genetic variants associated with infliximab response. Candidate variants were validated in 77 German patients with IBD. Stepwise multivariate logistic regression was performed to identify predictors. Results We found five candidate variants that were associated with primary nonresponse to infliximab (P < 5 × 10−6). Of the five variants, rs2228273 in ZNF133 was validated in German (combined P = 6.49 × 10−7). We also identified the best genetic variant (rs9144, P = 4.60 × 10−6) associated with the loss of infliximab response. In multivariate regression analysis, rs2228273 (P = 2.10 × 10−5), concurrent azathioprine/6‐mercaptopurine use, and bodyweight at the first infliximab use (< 50 kg) were associated with primary nonresponse. In addition, the Crohn's disease activity index at the first infliximab use and rs9144 (P = 0.001) were independently associated with the loss of response in patients with Crohn's disease. Conclusions We identified clinical and genetic markers associated with infliximab response in IBD patients. Our findings could provide insights to maximize the efficacy of infliximab therapy in IBD patients.

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“…Epithelial-derived IL-33 could directly act on Th17 cells to help them to acquire immunosuppressive phenotype(44). In addition, IL-33 induced M2 macrophages has been reported in the contribution of attenuation of colitis(45, 46). Th2 cytokines also appear to influence resolution of inflammation by inducing polarization of macrophages to M2 macrophages (45).…”

Section: Discussionmentioning

confidence: 99%

IL-33 regulates gene expression in intestinal epithelial cells independently of its nuclear localization

Chen

Furtado

Lira

2018

Preprint

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IL-33 is a cytokine found in the extracellular space (mature IL-33) or in the cell nucleus (full-length IL-33). Nuclear accumulation of IL-33 has been reported in intestinal epithelial cells (IEC) during intestinal inflammation and cancer, but a functional role for this nuclear form remains unclear. To study the role of nuclear IL-33 in IEC, we generated transgenic mice expressing full-length IL-33 in the intestinal epithelium (Vfl33 mice). Expression of full-length IL-33 in the epithelium resulted in accumulation of IL-33 protein in the nucleus and secretion of IL-33. Over-expression of full-length IL-33 by IEC did not promote gut inflammation, but induced expression of genes in the IEC and lamina propria lymphocytes (LPL) that correlated negatively with genes expressed in inflammatory bowel diseases (IBD). Because the IL-33 receptor ST2 is expressed by IEC, there was the potential that both the mature and full-length forms could mediate this effect. To specifically interrogate the transcriptional role of nuclear IL-33, we intercrossed the Vfl33 mice with ST2-deficient mice. ST2 deficiency completely abrogated the transcriptional effects elicited by IL-33 expression, suggesting that the transcriptional effects of IL-33 on IEC are mediated by its mature, not its nuclear form.HighlightsExpression of full-length IL-33 in the epithelium resulted in accumulation of IL-33 protein in the nucleus and secretion of IL-33.Full-length IL-33 induced differential gene expression in IEC and LPL that was negatively associated with intestinal inflammatory diseasesIL-33 regulated gene expression in IEC via its extracellular (mature) form not via its nuclearform.

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Interleukin-33 regulates intestinal inflammation by modulating macrophages in inflammatory bowel disease

Cited by 90 publications

References 59 publications

IL-33 and the intestine: The good, the bad, and the inflammatory

IL-33 and the intestine: The good, the bad, and the inflammatory

ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases

IL-33 regulates gene expression in intestinal epithelial cells independently of its nuclear localization

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