Tu1860 Inverse Expression of IL-33 in TH1 Versus TH2 Mediated Experimental Colitis

Abstract

Background: Interleukin (IL)-33 is a pro-inflammatory cytokine that has been associated with induction of human T helper 2 (TH2)-type inflammatory responses through activation of the ST2 receptor. Recent research has shown that IL-33 is upregulated in active ulcerative colitis (UC), but the role of IL-33 in regulation of intestinal mucosal immunologic reactions is uncertain. Aim: The aim of the present study was to describe the regulation of IL-33 in a TH1 and a TH2 model of experimental colitis, to determine if IL-33 is also regulated according to the T helper cell profile in the inflamed intestinal mucosa. Methods: Expression of IL-33 was investigated in dextran sodium sulphate (DSS)-induced colitis (a TH2-type of inflammation) and in the T-cell transfer model of colitis (SCID colitis) (a TH1-type of inflammation). The colonic IL-33 mRNA expression was analyzed by a quantitative realtime polymerase chain reaction (qRT-PCR). IL-33 protein expression and its localization were investigated by immunoblotting and by standard immunohistochemical procedures. The association between IL-33 expression and clinical outcome measures including the disease activity index (DAI), colon length, and histological inflammation scores was determined. Results: The colonic IL-33 mRNA expression was significantly up-regulated in the experimental DSS colitis model (p<0.05), and significantly down-regulated in the SCID colitis (p<0.01). Our results showed an increased number of IL-33 positive cells in DSS colitis localized to lamina propria inflammatory cells, whereas IL-33 protein expression in SCID colitis was abolished. IL-33 expression correlated positively with the DAI-score (p<0.001), colon length (p<0.001), and the histological inflammation score (p<0.001) of the DSS model. Conclusions: The present study demonstrates that colonic IL-33 expression in mice is highly dependent on the type of mucosal inflammatory response induced, being high in TH2-type inflammatory conditions, and low in TH1-type inflammatory responses. IL-33 might be a key determinant of the nature of the colonic mucosal inflammation and thus be of importance for the development of inflammatory bowel disease. Inhibition of IL33 signalling could in this way be a potential therapeutic target in UC which is driven by a TH2-type inflammatory reaction.