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J. Biol. Chem., Vol. 283, Issue 3, 1713-1722, January 18, 2008

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Nitric-oxide Synthase 2 Interacts with CD74 and Inhibits Its Cleavage by Caspase during Dendritic Cell Development^*

Dachuan Huang, Deyu Tarika Cai, Rong Yuan Ray Chua, David Michael Kemeny, and Siew Heng Wong¹

From the Laboratory of Membrane Trafficking and Immunoregulation, Department of Microbiology, Yong Loo Lin School of Medicine, and the Immunology Programme, National University of Singapore, Singapore 117597, Republic of Singapore

Dendritic cells (DC) are professional antigen-presenting cells that possess specific and efficient mechanisms to initiate immune responses. Upon encounter with pathogens, immature DC will go through a maturation process that converts them to highly immunogenic mature DC. Despite the fact that nitric oxide (NO) was produced in large amounts in maturing DC, it is still unclear whether NO is the key molecule that initiates and enhances DC maturation and T cell proliferation, respectively. Here, we report that NO donor and overexpression of either nitric-oxide synthase 2 (NOS2) or nitric-oxide synthase 3 (NOS3) alone can induce surface expression of major histocompatibility complex class II (MHC II) and both the essential co-stimulatory molecules CD80 and CD86 in immature DC. Consistently, NO donor-treated immature DC were capable of enhancing T cell proliferation in vitro in the absence of lipolysaccharide. Interestingly, NOS2 interacts with CD74 (the MHC II-associated invariant chain), and the degradation of CD74 by caspases in immature DC was inhibited upon treatment with NO donor. Because the trafficking of MHC II is CD74-dependent, the increase in cell surface localization of MHC II in maturing DC is in part due to the increase in CD74 protein expression in the presence of NOS2 and NO.

Received for publication, July 23, 2007 , and in revised form, November 1, 2007.

^* This work was supported by Microbiology Vaccine Initiative and Academic Research Council-Singapore Ministry of Education Grants R182-000-092-112 and R182-000-099-112 (to S. H. W.). 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: 03-14 Block MD4A, 5 Science Dr. 2, Singapore. Tel.: 65-6516-3517; Fax: 65-6776-6872; E-mail: micwsh{at}nus.edu.sg.

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