The spiral, microaerophilic, Gram-negative bacterium Helicobacter pylori (H. pylori) induces chronic gastritis and is a well known risk factor for peptic ulcer and gastric cancer. Although H. pylori infection can persist for decades, only a fraction of colonized individuals ever develop clinical diseases. Clinical outcome is influenced by a balance between H. pylori virulence factors and the host immune response. However, the mechanisms by which bacterial and/or host factors cause disease remain unclear. Identification of immune response genes that regulate the H. pylori-host interactions will not only have diagnostic and therapeutic implications, but may also provide insights into other inflammation related cancer.
Olfactomedin 4 down-regulates innate immunity against Helicobacter pylori infection. PNAS USA June 1 2010. doi: 10.1073/pnas.100126910
Olfactomedin 4 (OLFM4) is a glycoprotein that has been found to be up-regulated in inflammatory bowel diseases and Helicobacter pylori infected patients. However, its role in biological processes such as inflammation or other immune response is not known. In this study, we generated OLFM4 KO mice to investigate potential role(s) of OLFM4 in gastric mucosal responses to H. pylori infection. H. pylori colonization in the gastric mucosa of OLFM4 KO mice was significantly lower compared with WT littermates. The reduced bacterial load was associated with enhanced infiltration of inflammatory cells in gastric mucosa. Production and expression of proinflammatory cytokines/chemokines such as IL-1β, IL-5, IL-12 p70, and MIP-1α was increased in OLFM4 KO mice compared with infected controls. Furthermore, we found that OLFM4 is a target gene of NF-κB pathway and has a negative feedback effect on NF-κB activation induced by H. pylori infection through a direct association with nucleotide oligomerization domain-1 (NOD1) and -2 (NOD2). Together these observations indicate that OLFM4 exerts considerable influence on the host defense against H. pylori infection acting through NOD1 and NOD2 mediated NF-κB activation and subsequent cytokines and chemokines production, which in turn inhibit host immune response and contribute to persistence of H. pylori colonization.