Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease

Beltrán, Caroll J.; Núñez, Lucı́a; Díaz-Jiménez, David; Farfan, N.; Candia, Enzo; Heine, Claudio; López, Francisco; González, Marı́a Julieta; Quera, Rodrigo; Hermoso, Marcela A.

doi:10.1002/ibd.21175

Cited by 205 publications

(252 citation statements)

References 37 publications

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“…In the tumor stroma IL-33 immunoreactivity can also be identified in microvessels and myfibroblasts, this observation is consistent with previous findings from studies in patients with ulcerative colitis (30,(43)(44)(45). In those studies, IL-33 immunoreactivity was observed in both the inflamed colonic epithelium and lamina propria.…”

Section: Discussionsupporting

confidence: 92%

“…In the investigation of IL-33 in colonic diseases, it has been found that the increase of IL-33 is related to the development of colorectal chronic inflammation (ulcerative colitis) (29,30), whereas the epidemiological studies from different countries have revealed that ulcerative colitis may significantly raise the CRC risk (33)(34)(35)(36)(37)(38)(39). Our current study, in our best knowledge, is the first study to demonstrate a dynamic change of IL-33 from the colorectal adenomas to the sporadic CRCs.…”

Section: Discussionmentioning

confidence: 59%

“…In human HCC, no significant difference in IL-33 serum levels was found in HCC compared to liver cirrhosis and healthy controls (28). The role of IL-33 in inflammatory bowel diseases has been studied, extensive evidence now suggests that IL-33 is activated in the inflamed mucosa of ulcerative colitis and plays a critical role in the development of chronic inflammation (29,30), which is a risk factor for CRC. However, information is still very limited regarding the IL-33/ST2 axis in sporadic colorectal tumor-bearing hosts, particularly regarding the changes in the colorectal adenoma-carcinoma sequence.…”

Section: Introductionmentioning

confidence: 99%

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Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer

Cui

Gundersen

et al. 2014

Cancer Immunol Immunother

108

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Most sporadic colorectal cancers (CRCs) develop from preexisting adenomas. The transition from an adenoma to a CRC leads to disruption in cytokine secretion and immune imbalance.Interleukin-33 (IL-33) is a newly discovered proinflammatory cytokine belonging to the IL-1 cytokine family, and involved in the regulation of immune function and development of chronic colorectal inflammation and cancers. However, the activation of the IL33/ST2 axis alongside the colorectal adenoma-carcinoma sequence is poorly understood. Our aim is to evaluate the dynamics between the IL-33/ST2 axis and the human colorectal normaladenoma -carcinoma sequence. The expression of IL-33 in adenomas (n=50) determined by real-time PCR was significantly higher than that in the colorectal mucosa from normal individuals. The expression of IL-33 was also increased in CRCs (n=50) when compared to the normal control group. Significantly lower levels of IL-33 where found in the CRCs compared with the adenomas; moreover, the analysis revealed that a high IL-33 level was associated with a low dysplasia degree in the adenomas, as well as with a statistically nonsignificant increase of survival time in the CRC patients. The increased expression of IL-33 in adenomas/CRCs was confirmed by immunohistochemistry (IHC) which showed that IL-33 immunoreactivity was expressed in the adenomatous/cancerous epithelium, whereas it was undetectable in the normal controls. IHC also confirmed that the IL-33 receptor (ST2) is increased in tumor stromal cells. Double IHCs identified that IL-33 immunoreactivity was in the tumor stromal myofibroblasts and microvessels. In conclusion, the expression of IL-33 in the tumor microenvironment was dynamically altered along the colorectal adenomacarcinoma sequence; and may be a potential predictor for the progression of the adenoma to the CRC.3

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer

Cui

Gundersen

et al. 2014

Cancer Immunol Immunother

108

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“…Robust data indicate that IL-33 expression is increased in the inflamed mucosa of IBD patients versus healthy controls, particularly in UC [Beltran et al 2010;Kobori et al 2010;Pastorelli et al 2010;Seidelin et al 2010]. Mucosal expression of IL-33 is mostly localized to nonhematopoietic cells, particularly intestinal epithelial cells [Beltran et al 2010; Pastorelli et al 2010; Seidelin et al 2010] and myofibroblasts [Kobori et al 2010] (Figures 2A and C).…”

Section: Introductionmentioning

confidence: 92%

“…Less was known regarding the importance of this cytokine in the maintenance of intestinal homeostasis and its potential role in gut-associated diseases. However, in 2010, four independent groups reported the association of IL-33 with IBD, with elevated expression specifically in UC patients [Beltran et al 2010;Kobori et al 2010;Pastorelli et al 2010;Seidelin et al 2010]. Although emerging data is beginning to uncover the precise function of IL-33 in the gastrointestinal (GI) tract, little has been established that mechanistically addresses the role of IL-33 during normal gut homeostasis as well as during IBD.…”

Section: Introductionmentioning

confidence: 99%

Novel cytokine signaling pathways in inflammatory bowel disease: insight into the dichotomous functions of IL-33 during chronic intestinal inflammation

Pastorelli

Salvo

Cominelli

et al. 2011

Therap Adv Gastroenterol

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In 2010, four independent groups almost simultaneously reported the association of the novel interleukin-1 (IL-1) family member, IL-33, with inflammatory bowel disease (IBD). The findings were remarkably consistent and demonstrated that IL-33 is markedly upregulated in, and specific to, ulcerative colitis (UC). In addition, although a variety of gut-associated immune cell subsets express IL-33, the primary source appears to be the intestinal epithelium. IL-33's receptor, ST2, a formerly orphaned IL-1 receptor-related protein, was also found to be increased in UC patients, although the cellular source of ST2 appears to be somewhat more ambiguous. In fact, emerging evidence indicates that the IL-33/ST2 axis plays a critical role in several other chronic inflammatory and immune disorders. In the gut, IL-33 has been shown to be important in the clearance of intestinal parasites, and inducing epithelial cell hyperplasia, mucus production and mucosal eosinophilic infiltration. However, despite the established trend of increased IL-33 and ST2 expression during IBD, specifically UC, the precise pathophysiologic relevance of these findings has yet to be determined. Interestingly, IL-33 has the ability to potentiate pathogenic Th2 and Th17 responses in gut-associated lymphoid tissues, while also promoting healing of damaged mucosa following inflammatory insults. Indeed, further mechanistic studies are warranted to confirm the possible dichotomous functions of IL-33 during chronic intestinal inflammation and better define its precise role in the pathogenesis of IBD. Herein, we discuss what is currently known about IL-33/ST2 in the gut and speculate as to the potential role of the IL-33/ST2 system in IBD.

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TGF‐β limits IL‐33 production and promotes the resolution of colitis through regulation of macrophage function

Rani

Smulian

Greaves³

et al. 2011

Eur J Immunol

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Summary Macrophages promote tissue injury or repair depending upon on their activation status and the local cytokine milieu. It remains unclear whether the immunosuppressive effects of transforming growth factor beta (TGF-β) serve a non-redundant role in macrophage function in vivo. We generated macrophage-specific transgenic mice that express a truncated TGF-β receptor II under control of the CD68 promoter (CD68TGF-βDNRII)and subjected these animals to the dextran-sodium sulfate (DSS) model of colitis. CD68TGF-βDNRII mice have an impaired ability to resolve colitic inflammation as demonstrated by increased lethality, granulocytic inflammation, and delayed goblet cell regeneration compared to transgene negative littermates. CD68TGF-βDNRII mice produce significantly less interleukin 10, but have increased levels of IgE and IL-33+ macrophages than controls. These data are consistent with associations between ulcerative colitis and increased IL-33 production in humans and suggests that TGF-β may promote the suppression of intestinal inflammation, at least in part, through direct effects on macrophage function.

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Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease

Abstract: The novel association between the ST2/IL-33 system and IBD seems to identify that variations in this axis might regulate the inflammatory process in these diseases.

Cited by 205 publications

References 37 publications

Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer

Dynamics of the IL-33/ST2 network in the progression of human colorectal adenoma to sporadic colorectal cancer

Novel cytokine signaling pathways in inflammatory bowel disease: insight into the dichotomous functions of IL-33 during chronic intestinal inflammation

TGF‐β limits IL‐33 production and promotes the resolution of colitis through regulation of macrophage function

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