The mucosal immune and inflammatory response to gastric Helicobacter infection. Interleukin-10 (IL-10) is a cytokine with potent anti-inflammatory and immune regulatory activity. We previously reported that IL-10 deficient mice (IL10-/-) develop a spontaneous inflammatory bowel disease, indicating that IL-10 is a central regulator of the mucosal immune response in the colon. We therefore investigated whether IL-10 is an important regulator of the immune response to gastric Helicobacter pylori infection. H. pylori infection is the major etiologic agent of peptic ulcer disease. In addition, chronic H. pylori infection can lead to epithelial changes that are precursors for the development of gastric adenocarcinoma. To study the role of IL-10 in the host response to gastric Helicobacter infection, stomachs of IL10-/- and wild-type mice were colonized with Helicobacter felis. We found that H. felis-infected wild-type mice developed mild gastric inflammation; in contrast, H. felis-infected IL10-/- mice develop severe hyperplastic gastritis, characterized by a dense infiltration of large numbers of CD4+ T cells and macrophages. Moreover, H. felis infected IL10-/- mice develop striking alterations in the gastric epithelium including loss of parietal and chief cells, focal production of acidic mucins, and marked epithelial proliferation with features of dysplasia, similar to what can be found in individuals with chronic H. pylori infection. Our present studies are focusing on the role of inflammatory cytokines and immune effector cells in the immune response to gastric Helicobacter infection.
The role of prostaglandins in the regulation of the mucosal immune and inflammatory response. Inflammatory bowel disease (IBD) is a common disorder characterized by chronic inflammation in the gastrointestinal tract. IL10-/- mice develop a spontaneous inflammatory bowel disease that has histologic and immunologic similarities to human IBD. However, the development of IBD in IL10-/- mice takes 3-6 months, indicating the presence of other regulators of the mucosal immune and inflammatory response. One potential class of regulators of mucosal inflammation is prostaglandins, which are bioactive lipid mediators that are produced in large amounts during the inflammatory response. To study the role of IL-10 in the regulation of prostaglandin production during the acute inflammatory response, we evaluated LPS-induced cyclooxygenase expression and prostaglandin production in wild-type (wt) and IL10-/- mice. LPS-induced PGE2 production from IL10-/- spleen cells was 5.6-fold greater than that from wt spleen cells. LPS-stimulation resulted in the induction of COX-2 mRNA and protein in both wt and IL10-/- spleen cells, however, the magnitude of increase in COX-2 mRNA was 5.5-fold greater in IL10-/- mice as compared to wt mice. COX-1 protein levels were not affected by LPS stimulation in either wt or IL10-/- mice. These findings indicate that, in addition to IL10’s central role in the regulation of inflammatory cytokines, endogenous IL-10 is an important regulator of prostaglandin production in the response to LPS. We have found that COX-2 expression and PGE2 production in the colon is markedly increased in IL10-/- mice. Interestingly, we have found that treatment of IL10-/- mice with NSAIDs (which inhibit prostaglandin production) induces rapid development of severe inflammation, suggesting that prostaglandins are key down-regulators of the mucosal immune and inflammatory response in IL10-/- mice. Current studies are focused on the mechanisms by which COX-1 and COX-2 derived prostaglandins regulate the mucosal immune system.
