P204 - ABILITY OF THERAPEUTIC TREATMENT TO AMELIORATE THE PRO-COLITOGENIC EFFECTS OF IL-15 DURING COLITIS
19 Jan 18
5:30 PM
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7:00 PM
Dysregulated host-microbial interactions leading to an imbalance between harmful and protective intestinal bacteria (dysbiosis) is largely responsible for the rising incidence of inflammatory bowel disease (IBD), but the mechanisms remain poorly understood. In particular, low levels of the anti-inflammatory short chain fatty acid (SFCA) butyrate, which is a potent histone deacetylase inhibitor (HDACi) have been implicated in IBD pathogenesis. We recently showed that villin interleukin 15 transgenic (vIL-15tg) mice, which similar to IBD patients overexpresses IL-15 in the intestinal epithelium, have a higher susceptibility to colitis associated with a significant decrease in butyrate producing bacteria and butyrate production. We have unpublished data that v-IL-15tg mice show both, a significant IL-15-dependent expansion of cytotoxic GranzymeB+ NKG2D+ intraepithelial lymphocytes (IELs) and display increased HDAC activity in the gut epithelium. Here will test the hypothesis if therapeutic interventions (butyrate/HDACi treatment) revert the pro-inflammatory effects of IL-15 during colitis. We evaluated the disease severity (weight loss, histology) in two independent models of colitis (DSS and adoptive transfer colitis) and defined the efficacy of butyrate/HDACi treatment in IL-15-mediated ileo-colitis. IELs were isolated and analyzed by flow cytometry and RT-PCR. Our results indicate that butyrate, via it’s HDACi function, can significantly suppress both the disease severity during the in vivo models of ileo-colitis and the IL-15-mediated expansion of cytotoxic GranzymeB+ NKG2D+ IELs in v-IL-15tg mice (see schematic). In summary, our results show that IL-15 mediates it’s pathogenic effects via a HDAC-dependent mechanism during colitis. Our studies will provide support to identify IBD patients with high IL-15 expression and provide a basis for therapeutic strategies aimed at increasing butyrate expression to treat these patients.