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BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that has recently been implicated to play a role in carcinogenesis in a variety of systems. MIF regulates both innate and adaptive immune responses and can alter cell cycle events by inhibiting p53 function. H. pylori, which is closely linked to gastric cancer, induces the gastric epithelium to produce MIF. MIF has been shown to bind to CD74, which we have shown to be highly expressed on the surface of gastric epithelial cells during H. pylori infection. Clinical studies have also shown that CD74 expression is increased in gastric cancer patients. Since H. pylori infection induces both MIF production and CD74 surface expression by gastric epithelial cells, and this receptor and ligand are highly expressed during gastric cancer, we hypothesized that H. pylori-induced MIF binds to CD74 on gastric epithelial cells and Induces Erk phosphorylation and cell proliferation. METHODS: MIF production by gastric epithelial cells was assed by ELISA. Biotinylated MIF binding to CD74 on gastric epithelial cells was verified by flow cytometry. Cell proliferation was measured by after treatment with recombinant MIF and H. pylori by MTS assay. Erk1/2 phosphorylation was measured by Bioplex bead array. RESULTS: N87 and HS-738 gastric epithelial cells produced MIF in response to H. pylori. Biotinylated MIF bound to gastric epithelial cells, but very little binding was observed when CD74 was blocked with monoclonal antibodies. Recombinant MIF and H. pylori increased cell proliferation and Erk1/2 phosphorylation, which was decreased by anti-CD74 antibodies or anti-MIF neutralizing antibodies. CONCLUSION: H. pylori-induced MIF production by the gastric epithelium results in ERK 1/2 phosphorylation and cell proliferation as a result of MIF binding to surface CD74, which is increased during infection. This autocrine process may represent an important link between H. pylori infection and associated gastric neoplasia.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]