The etiology of Crohn's disease (CD) and ulcerative colitis (UC), the major forms of inflammatory bowel diseases (IBD) in humans, remains unknown, but evidence suggests that IBD results from the interaction of genetic and environmental factors that ultimately promote an abnormal immune response leading to organ damage.¹ x 1 Kaser, A., Zeissig, S., and Blumberg, R.S. Inflammatory bowel disease. Annu Rev Immunol. 2010; 28: 573–621 Crossref | PubMed | Scopus (945) | Google Scholar See all References

Background and Aim. 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 of salt-enriched diet on the course of IBD remains unknown. In this study we examined whether high salt intake alters mucosal cytokine production and exacerbates colitis. Methods. Normal intestinal lamina propria mononuclear cells (LPMC) were activated with anti-CD3/CD28 in the presence or absence of increasing concentrations of sodium chloride (NaCl) and/or SB202190, a specific inhibitor of p38/MAP Kinase. For in vivo experiments, high dose of NaCl was administered to mice 15 days before induction of trinitrobenzene-sulfonic acid (TNBS)-colitis or dextran sulfate sodium (DSS)-colitis. In parallel, mice were given SB202190 before induction of TNBS-colitis. Transcription factors and effector cytokines were evaluated by flow-cytometry and real-time PCR. Results. IL-17A, IL-23R, TNF-α and Ror-γ T were significantly increased in human LPMC following NaCl exposure while there was no significant change in IFN-γ, T-bet and Foxp3. Pharmacologic inhibition of p38/MAPK abrogated the NaCl-inducing effect on LPMC-derived cytokines. Mice receiving high salt diet developed a more severe colitis than control mice and this effect was preventable by SB202190. Conclusions. Data indicate that exposure of intestinal mononuclear cells to high NaCL enhances effector cytokine production and contributes to exacerbate experimental colitis in mice.

Background. We previously demonstrated that in inflammatory bowel disease (IBD) there is enhanced production of interleukin (IL)-21, a cytokine that act

Crohn's disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD) in man, are thought to be caused by an excessive and poorly controlled immune response that is directed against components of the normal microflora. The exact sequence of events by which this pathological process is triggered and maintained is not fully understood, but studies in experimental models of IBD and data emerging from recent clinical trials indicate that T cell-derived cytokines are crucial mediators of the tissue damage. Although CD and UC have been traditionally considered two typical examples of T helper (Th)1 or Th2-associated disease respectively, it is now known that CD- and UC-related inflammation is also marked by enhanced production of cytokines made by a distinct subset of Th cells, termed Th17 cells. Th17 cytokines can have both tissue-protective and inflammatory effects in the gut and there is evidence that Th17 cells can alter their cytokine program according to the stimuli received and convert into Th1-producing cells. These novel findings have contributed to advancing our understanding of mechanisms of gut tissue damage and open new avenues for development of therapeutic strategies in IBD.

Fibrostrictures (FS) are a major complication of Crohn's disease (CD). Pathogenesis of FS is not fully understood, but activation of fibroblasts and excessive collagen deposition are crucial in the development of FS. Here, we investigated the role of aryl hydrocarbon receptor (AhR) in intestinal fibrosis. AhR RNA and protein expression were evaluated in intestinal fibroblasts of CD patients and controls. CD fibroblasts were stimulated with TGF‐β1 or TNF‐α in the presence or absence of the AhR activator Ficz, an AhR antagonist CH223191, or a specific AhR‐silencing RNA. In CD fibroblasts, TGF‐β1 and TNF‐α increased Col1A1, Col3A1 and α‐SMA transcripts and collagen secretion and this effect was reduced by Ficz and upregulated by CH22319. TGF‐β1 or TNF‐α induced activation of p38 and ERK1/2 MAP kinases was decreased by Ficz and increased by CH223191. The inhibitory effect of Ficz on Map kinase activation and collagen induction was abolished by AhR silencing. To assess the role of AhR in vivo, mice with trinitrobenzene‐sulfonic‐acid induced colonic fibrosis were given Ficz or CH223191. Mice given either Ficz or CH223191 produced less or more collagen respectively as compared with control mice. Our results indicate that AhR is a negative regulator of profibrotic signals in the gut.