Editors' ChoiceColitis

A Punch to the Gut: IL-9 Promotes Ulcerative Colitis

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Science Translational Medicine  18 Jun 2014:
Vol. 6, Issue 241, pp. 241ec106
DOI: 10.1126/scitranslmed.3009595

Ulcerative colitis (UC) and Crohn’s disease (CD) are the two most common forms of inflammatory bowel diseases (IBDs). IBD patients often posses abnormalities in adaptive immunity, particularly in CD4+ T helper (TH) cells, although evidence has suggested that different subsets of TH cells may be preferentially involved in the pathogenesis of UC and CD. Gerlach et al. have demonstrated in a recent paper that a subset of TH cells, interleukin-9 (IL-9)–producing TH9 cells, contributed specifically to the disease development in UC.

The authors first found that both IL-9 message and IL-9–producing CD4+ cells were significantly up-regulated in the lamina propria of UC patients but not in those of CD patients or healthy subjects. Furthermore, UC patients had higher numbers of CD4+ cells expressing PU.1, a critical transcription factor for the development of TH9 cells and elevated IL-9 receptor expression on intestinal epithelial cells. To study the function of IL-9 in UC, the authors used a mouse oxazolone-induced colitis model and found that IL-9 was mainly produced by mucosal lymphocytes in this model. Importantly, IL-9–deficient mice or mice treated with an IL-9–neutralizing antibody had more greatly reduced colitis than their controls, suggesting that IL-9 is a key factor contributing to disease development in UC. Using a series of elegant in vivo and in vitro experiments, the authors went on to demonstrate that IL-9 promoted colitis through its effects on the amplification of mucosal inflammation and the regulation of intestinal barrier function. Strikingly, the authors also showed that IL-9 was of critical relevance in the settings of chronic intestinal diseases because the blockade of IL-9 function reduced disease severity in two mouse models of chronic colitis.

These findings have identified IL-9 as a pathogenic factor in UC and thus have greatly improved our understanding on the molecular etiology of UC. It will be informative in the future to determine whether the levels of IL-9 or TH9 cells in UC patients positively correlate with their clinical scores in larger scale of clinical studies. Nevertheless, the results in this paper promise to open the door to new UC therapeutics targeting the IL-9 pathway.

K. Gerlach et al., TH9 cells that express the transcription factor PU.1 drive T cell–mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat. Immunol., published online 8 June 2014 (10.1038/ni.2920). [PubMed]

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