Interleukin-33 Ameliorates Experimental Colitis through Promoting Th2/Foxp3+ Regulatory T-Cell Responses in Mice

Abstract

Crohn's disease (CD) is characterized by the activation of Th1 and Th17 cells and deficiency of regulatory T cells (Tregs), leading to intestine tissue injury and destruction. As a novel cytokine of the interleukin (IL)-1 family, the role and underlying mechanisms of IL-33 in CD remain poorly understood. Here, we assess the effects and mechanisms of IL-33 on the trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis that mimics human CD. We found that IL-33 levels were increased in the TNBS-treated mice, whereas recombinant IL-33 (rIL-33) administration substantially ameliorated TNBS-mediated colonic tissue injury and clinical symptoms of colitis. The protective effect of rIL-33 was partly associated with the markedly increased induction of Th2-type cyto kines. Importantly, rIL-33 treatment resulted in prominently upregulated Foxp3 expression in the TNBS-treated mice, and depletion of Tregs significantly abrogated the impact of IL-33 on reducing the development of colitis. Notably, the level of CD103 + dendritic cells (DCs), which promotes development of Tregs, is also increased in mesenteric lymph node and lamina propria of rIL-33-treated mice. The impact of rIL-33 on CD103 + DC induction was the result of indirectly upregulating intestine epithelial cells that produce thymic stromal lymphopoietin and retinoic acid but do not directly act on DCs. In conclusion, our data provide clear evidence that IL-33 plays a protective role in TNBS-induced colitis, which is closely related to a Th1-to-Th2/Treg switch. Thus, IL-33 is a promising candidate for the development of new treatments for CD.

Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation

“…Finally, the IL-33 treatment regimen provided functional benefit alleviating the sensorimotor deficits induced by pMCAo. Our data are in line with previously reported beneficial function of IL-33 in a mouse model of SCI (Pomeshchik et al, 2014), EAE (Duan et al, 2012) and atherosclerosis (Miller et al, 2008).…”

“…Since Tregs were shown to mediate the protective effects of IL-33 in EAE (Duan et al, 2012) and the lack of IL-33 signaling reduced the amount of Tregs in atherosclerotic mice (Wasserman et al, 2012), Tregs were potential candidates for mediating the IL-33-induced protection. To our surprise, depletion of Tregs failed to prevent IL-33 induced protection after pMCAO.…”

“…Since Tregs ameliorate ischemia-induced cell death (Liesz et al, 2009), we assessed whether Tregs are underlying the IL-33-mediated protection by depletion of Tregs according to a previously published regimen using an anti-CD25 antibody (Duan et al, 2012). To ensure that the depletion of Tregs was successful, the number of CD25 positive cells was analyzed from the blood samples of the ischemic mice.…”

The role of IL-33/ST2L signals in the immune cells

“…Consistent with this study, St2 is also identified as one of the top differentially unregulated genes in colonic Treg cells [26]. There are several published reports showing that administration of recombinant IL-33 led to a significant increase in the frequency and total number of splenic Treg cells [25,26,49,51]. However, Treg induction by IL-33 is TGF-␤1 dependent, as addition of IL-33 to iTreg cultures significantly increases both the percentage and total number of Foxp3-expressing cells but has no effect on Foxp3 expression in the absence of TGF-␤1 [26].…”

“…A large number of evidences have supported its pathogenic role in arthritis [21], asthma [22], colitis [23], and acute kidney injury [24]. However, protective role for IL-33 has also been described in murine models of acute colitis [25,26], experimental autoimmune uveitis [27] and chronic cardiac rejection model [28].…”