Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice

To elucidate the pathogenesis of Helicobacter pylori-associated gastritis, we studied immune responses of C57BL/6J wild-type (WT), SCID, and gene defi cient (IFN-gamma(-/-) and IL-4(-/-)) mice following infection with a pathog enic isolate of H. pylori (SPM326). During early infection in WT mice, mono nuclear and polymorphonuclear cells accumulated in the gastric lamina propr ia, and the numbers of cells in the inflamed mucosa expressing IFN-gamma, b ut not IL-4, mRNA rose significantly (p < 0.005), consistent with a local T h1 response. Splenic T cells from the same infected WT mice produced high l evels of IFN-gamma, no detectable IL-4, and low amounts of IL-10 following in vitro H. pylori urease stimulation, reflecting a systemic Th1 response, Infected C57BL/6J SCID mice did not develop gastric inflammation despite co lonization by many bacteria, Infected C57BL/10J and BALB/c mice also did no t develop gastric inflammation and displayed a mixed Th1/Th2 splenic cytoki ne profile. These data imply a major role for the Th1 cytokine IFN-gamma in H. pylori-associated gastric inflammation in C57BL/6J mice. Compared with WT animals, infected IL-4(-/-) animals had more severe gastritis and higher levels of IFN-gamma production by urease-stinulated splenocytes (p < 0.01) , whereas IFN-gamma(-/-) mice exhibited no gastric inflammation and higher levels of IL-4 production by stimulated splenocytes, These findings establi sh C57BL/6J mice as an important model for H, pylori infection and demonstr ate that up-regulated production of IFN-gamma, in the absence of the opposi ng effects of IL-4 land possibly IL-10), plays a pivotal role in promoting H. pylori-induced mucosal inflammation.