Published online before print March 12, 2009

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080708

Accepted for publication December 22, 2008.

Article

Essential Role for Macrophage Migration Inhibitory Factor in Gastritis Induced by Helicobacter pylori

Benny L.W. Wong^*, Sen-Lin Zhu^*, Xiao R. Huang^*, Juan Ma^*, Harry H.X. Xia^*, Richard Bucala, Benjamin C.Y. Wong^*, and Hui Yao Lan^*@

From the Department of Medicine,* The University of Hong Kong, Hong Kong, China; the Department of Gastroenterology, First Affiliated Hospital, Sun Yat-Sen University, Guangzha, China; the Division of Gastroenterology and Hepatology, Guangdong Provincial People's Hospital, Guangzhou, China; and the Yale University School of Medicine, New Haven, Connecticut

^@ To whom correspondence should be addressed. E-mail: hylan{at}hku.hk.

	Abstract

Macrophage migration inhibitory factor (MIF) is an upstream regulator of immune and inflammatory responses; however, its role in Helicobacter pylori (HP)-associated gastritis remains unknown. We infected MIF knockout (KO) and wild-type mice with SS1 HP and found that 2 weeks after infection, MIF and its receptor CD74 were markedly up-regulated in wild-type mice. This up-regulation preceded the up-regulation of both tumor necrosis factor- and intercellular adhesion molecule-1, as well as the development of moderate gastritis at 8 weeks, as determined by a significant infiltration of neutrophils, T cells, and macrophages. In contrast, KO mice were protected against HP-induced gastritis by preventing the up-regulation of CD74 and Th1-mediated immune injury, including a reduction in the Th1 transcriptional factor T-bet and the expression of interferon-. Additionally, inhibition of skin delayed type hypersensitivity reactions to HP antigens in KO mice also suggested a critical role for MIF in cell-mediated injury. A regulatory role for MIF in Th1-immune responses was further demonstrated by the finding that antigen-primed CD4⁺ T cells lacking MIF failed to differentiate into the Th1 phenotype; these cells were instead promoted to Th2 differentiation after challenge with HP antigen in vitro. Results from this study indicated that inhibition of HP-induced innate immune responses and Th1-mediated immune injury may be the key mechanisms by which KO mice failed to develop gastritis after HP infection.