IL-33, a member of the IL-1 cytokine family that signals through ST2, is upregulated in ulcerative colitis (UC); however, the role of IL-33 in colitis remains unclear. IL-33 augments type 2 immune responses, which have been implicated in UC pathogenesis. We sought to determine the role of IL-33 signaling in oxazolone (OXA) colitis, a type 2 cytokine-mediated murine model of UC.
Colon mucosal IL-33 expression was compared between pediatric and adult UC and non-IBD patients using immunohistochemistry and real-time PCR. OXA colitis was induced in WT, IL-33−/− and ST2−/− mice, and histopathology, cytokine levels, and goblet cells were assessed. Transepithelial resistance (TER) was measured across IL-33-treated T84 cell monolayers.
Colon mucosal IL-33 was increased in pediatric patients with active UC and in OXA colitis. IL-33−/− and ST2−/− OXA mice exhibited increased disease severity compared to WT OXA mice. OXA induced a mixed mucosal cytokine response, but few differences were observed between OXA WT and IL-33−/− or ST2−/− mice. Goblet cells were significantly decreased in IL-33−/− and ST2−/− OXA compared to WT OXA mice. IL-33 augmented TER in T84 cells, and this effect was blocked by the ERK1/2 inhibitor PD98,059.
OXA colitis is exacerbated in IL-33−/− and ST2−/− mice. Increased mucosal IL-33 in human UC and murine colitis may be a homeostatic response to limit inflammation, potentially through effects on epithelial barrier function. Further investigation of IL-33 protective mechanisms would inform the development of novel therapeutic approaches.