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TOLL-INTERACTING PROTEIN (TOLLIP) DECREASES THE SEVERITY OF ACUTE COLITIS
C Waterhouse1, D-M McCafferty2, P Kubes2
1Division of Paediatric Gastroenterology, 2Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta
BACKGROUND: The normal bacterial flora plays an important role for intestinal homeostasis and healing following injury. In predisposed animal and human hosts, however, dysregulated responses to intestinal bacteria lead to inflammatory bowel disease (IBD). Recognition of bacteria within the intestine is mediated, in part, through Toll-like receptors (TLRs). Toll-interacting protein (Tollip) is an intracellular protein known to modulate signaling via members of the interleukin (IL)-1 receptor superfamily including several TLRs. Most evidence indicates that Tollip acts as an inhibitor of myeloid differentiation primary response gene (MyD)88-dependent signaling following receptor activation. To date, no role for Tollip has been established in the intestinal inflammatory response. We hypothesized that Tollip deficiency would result in less severe inflammatory responses during acute colitis in mice.
EXPERIMENTAL DESIGN: Wild type (WT) or Tollip deficient (–/–) mice 8-12 weeks of age were treated with 4mg trinitrobenzene sulfonic acid (TNBS) in 30% ethanol per rectum for induction of colitis and followed for 7 days. Colonic tissue was taken for assessment of gross inflammatory scores, histological scores and myeloperoxidase (MPO) assay. Serum was obtained for multiple cytokine assessment using a Luminex assay.
RESULTS: Both WT and Tollip–/– mice developed colitis following TNBS administration. WT mice exhibited more severe weight loss as compared to Tollip–/– animals (16.6 vs. 11.3% weight loss by day 2, p < 0.05) that persisted until day 5. A trend was also seen to more severe gross scores of colonic inflammation and increased colonic MPO activity in WT animals that did not reach significance. Interestingly, several cytokines were increased in TNBS treated WT but not Tollip–/– animals on day 3, including IL-6 (4217.0 vs. 162.9 pg/ml; p < 0.05), granulocyte colony stimulating factor (10,160.0 vs 564.1 pg/ml; p < 0.01) and IL-17 (26.4 vs. 11.5 pg/ml; p < 0.05).
CONCLUSION: Tollip–/– mice show diminished clinical severity and cytokine production compared to WT animals during TNBS colitis. This highlights a unique role for Tollip in the early events during intestinal inflammatory responses. Ultimately, a better understanding of the role Tollip plays in the intestinal tract may provide insight into the pathogenesis of inflammatory bowel disease in susceptible individuals.