IL-33 Signaling Protects from Murine Oxazolone Colitis by Supporting Intestinal Epithelial Function.

Waddell A, Vallance JE, Moore PD, Hummel AT, Wu D, Shanmukhappa SK, Fei L, Washington MK, Minar P, Coburn LA, Nakae S, Wilson KT, Denson LA, Hogan SP, Rosen MJ
Inflamm Bowel Dis. 2015 21 (12): 2737-46

PMID: 26313694 · PMCID: PMC4654638 · DOI:10.1097/MIB.0000000000000532

BACKGROUND - 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.

METHODS - 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 was measured across IL-33-treated T84 cell monolayers.

RESULTS - 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 with 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 with WT OXA mice. IL-33 augmented transepithelial resistance in T84 cells, and this effect was blocked by the ERK1/2 inhibitor PD98,059.

CONCLUSIONS - 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.

MeSH Terms (20)

Adult Animals Child Colitis Colitis, Ulcerative Colon Cytokines Goblet Cells Humans Immunohistochemistry Interleukin-1 Receptor-Like 1 Protein Interleukin-33 Intestinal Mucosa Intestines Mice Oxazolone Real-Time Polymerase Chain Reaction Receptors, Interleukin Signal Transduction Up-Regulation

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