Helicobacter pylori causes gastric inflammation, peptic ulcer disease, and gastric cancer. Recent clinical and in vitro data indicate that both the cag pathogenicity island (PAI) and the outer inflammatory protein, OipA are involved in production of gastric mucosal interleukin (IL)-8 levels and the resulting inflammation. Published data aimed at understanding the cag PAl-associated IL-8 signal transduction pathway have provided inconsistent results possibly because the effect of OipA was not taken into account. This proposed study seeks to understand the IL-8 signal transduction pathway stimulated by H.pylori infection. I hypothesize that the oipA gene product activates the binding of interferon (IFN) regulatory factors (IREs) to a novel interferon-stimulated responsive element (ISRE)-like element in the IL-8 promoter and that the oipA gene product activates p38 mitogen-activated protein (MAP) kinase cascades, which the cag PAI does not. My approach involves use of parental H. pylori strains and precise gene deleted mutants of oipA, cag PAI, cagA, hopZ or oipA/cag PAI genes without polar effects, as well as complemented oipA mutants.
AIM 1 seeks to determine the mechanisms for regulation of IL-8 gene transcription in relation to OipA and cag PAI. I will test the hypothesis that OipA and/or cag PAI activates binding IRFs to the ISRE-like element, leading to IL-8 gene transcription. I will identify the MAP kinase pathways upstream of the IL-8 promoter related to OipA and the cag PAl. I will also determine whether there is cross-talk among the IRF-ISRE-Iike element pathway, the MAP kinase pathway, and IkappaB-NF-kappaB pathway upstream of the IL-8 promoter (i.e., are they linked or independent). Primary methods to be used include a) a luciferase reporter gene assay, b) electrophoretic mobility shift assays (EMSA) and supershift assay, e) microaffinity isolation assay, d) RNA interference, and e) western blot analysis.
AIM 2 seeks to confirm and extend the in vitro results by investigation of the in vivo effect of OipA and the cag PAI on gastric injury using the Mongolian gerbil model. I will determine the effect of OipA and cag PAl on gastric inflammation, clinical outcome, CXC chemokine (KC and IP- 10) induction and analyses of KC and IP- 10 promoter related to OipA and the cag PAL Primary methods to be used include a) real time reverse transcription-polymerase chain reaction, b) enzyme-linked immunosorbent assay, e) EMSA and supershift assay, and d) Western blot analysis. The results from these studies will provide new insights into the role of H. pylori in the pathogenesis of gastroduodenal disease.
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