High sodium chloride enhances inflammatory cytokine production in human and colitis in mice

Background:Environmental factors are supposed to play a decisive role in the pathogenesis of inflammatory bowel diseases (IBD).Increased dietary salt intake has been linked with the development of autoimmune diseases, but the impact that such an environmental factor has on the course of IBD remains unknown. In this study we investigated the cytokine response of intestinal immune cells to high concentrations of salt. Methods:Normal intestinal lamina propria mononuclear cells(LPMC) were activated with anti-CD3/CD28 with or without increasing concentrations (20-80 mM) of NaCL.In parallel, LPMC were treated as above in the presence or absence of  SB202190, a specific inhibitor of P38 activation. Transcription factor and effector cytokines were evaluated by flow-cytometry and real-time PCR. To examine if dietary NaCl intake influences the in vivo gut inflammation, high dose of NaCL (4% of the normal diet) was administered to mice 7 days before the induction of trinitrobenzene-sulfonic acid(TNBS)-colitis. Mice were then sacrificed at day 5 and LPMC and colon tissues were analyzed for inflammatory and anti-inflammatory molecules. Results:IL-17A and TNF-a were significantly increased in human LPMC following NaCl exposure while there was no significant change in IFN-g, IL-6, T-bet, RORgt and Foxp3. Pharmacologic inhibition of P38 abrogated the inducing effect of NaCL on LPMC-driven IL-17A and TNF-a production. Mice receiving high salt diet developed a more severe colitis following TNBS administration. Conclusions:High salt concentration enhances the production of inflammatory cytokine in the gut. Data provide novel insights into IBD pathogenesis and explain how high salt diet triggers/expands gut immune response.