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J. Biol. Chem., Vol. 283, Issue 5, 2784-2792, February 1, 2008

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Macrophage Migration Inhibitory Factor Induces B Cell Survival by Activation of a CD74-CD44 Receptor Complex^*

Yael Gore, Diana Starlets, Nitsan Maharshak, Shirly Becker-Herman, Utako Kaneyuki, Lin Leng¹, Richard Bucala¹, and Idit Shachar, Incumbent of the Dr. Morton and Ann Kleiman Professorial Chair²

From the Department of Immunology, the Weizmann Institute of Science, Rehovot 76100, Israel and the Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520

Macrophage migration inhibitory factor (MIF) is an upstream activator of innate immunity that regulates subsequent adaptive responses. It was previously shown that in macrophages, MIF binds to a complex of CD74 and CD44, resulting in initiation of a signaling pathway. In the current study, we investigated the role of MIF in B cell survival. We show that in B lymphocytes, MIF initiates a signaling cascade that involves Syk and Akt, leading to NF-B activation, proliferation, and survival in a CD74- and CD44-dependent manner. Thus, MIF regulates the adaptive immune response by maintaining the mature B cell population.

Received for publication, April 18, 2007 , and in revised form, November 5, 2007.

^* This work was supported in part by The Israel Science Foundation (founded by the Academy of Sciences and Humanities), the Migration and Targeting Cell Migration in Chronic Inflammation (MAIN) European Union Grant, the Israel Cancer Association, the Yale-Weizmann Foundation, and the Minerva Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported by National Institutes of Health Grants AR049610, AR050498, and AI042310 and the Alliance for Lupus Research.

² To whom correspondence should be addressed. Tel.: 972-8-934257; Fax: 972-8-9344141; E-mail: idit.shachar{at}weizmann.ac.il.

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