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J. Biol. Chem., Vol. 282, Issue 38, 27587-27597, September 21, 2007

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Leptin Induces CD40 Expression through the Activation of Akt in Murine Dendritic Cells^*

Queenie Lai Kwan Lam, Bo-Jian Zheng, Dong-Yan Jin^¶, Xuetao Cao^||, and Liwei Lu¹

From the Department of Pathology, the Centre of Infection and Immunology, and the ^¶Department of Biochemistry, The University of Hong Kong, Hong Kong, China and the ^||Institute of Immunology, Second Military Medical University, Shanghai, China

Increasing evidence suggests a regulatory role for leptin, an adipocyte-derived hormone, in immunity. Although recent studies indicated an essential role of leptin signaling in dendritic cell (DC) maturation, the molecular mechanisms by which leptin modulates DC functional maturation remained unclear. In this study, we showed that leptin induced CD40 expression in murine DC and significantly up-regulated their immunostimulatory function in driving T cell proliferation. Moreover, leptin markedly enhanced lipopolysaccharide-mediated DC activation. Using pharmacological inhibitors for Akt, STAT-1, or NF-B and the dominant negative forms of Akt and IB kinase //, as well as small interfering RNA for STAT-1, we showed that Akt, STAT-1, and NF-B were important for the leptinor lipopolysaccharide-induced CD40 expression. Coimmunoprecipitation analysis revealed that leptin promoted immune complex formation between Akt and the IB kinase subunits as well as STAT-1. Blocking the activity of Akt demonstrated a crucial role for Akt in translocation of STAT-1 and NF-B to the nucleus and activation of the CD40 promoter. Further analysis with chromatin immunoprecipitation assay confirmed that leptin recruited STAT-1, NF-Bp65, and RNA polymerase II to the CD40 promoter and enhanced histone 4 acetylation in a time-dependent manner. Thus, our results have elucidated the molecular mechanisms underlying leptin-induced CD40 expression and DC maturation.

Received for publication, June 4, 2007 , and in revised form, July 5, 2007.

^* This work was supported by grants from the National Natural Science Foundation of China, Council of Hong Kong Joint Research Scheme (Grants N-HKU 722/04, 30418017), and the National Key Basic Research Program of China (2001CB510002). 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.

¹ To whom correspondence should be addressed: Dept. of Pathology, the University of Hong Kong, Pokfulam Rd., Hong Kong, China. Tel.: 852-2855-4870; Fax: 852-2872-5197; E-mail: liweilu{at}hkucc.hku.hk.

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