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J. Biol. Chem., Vol. 279, Issue 11, 10776-10783, March 12, 2004

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Inhibition of Interleukin-12 p40 Transcription and NF-B Activation by Nitric Oxide in Murine Macrophages and Dendritic Cells^*

Huabao Xiong, Chen Zhu, Fengling Li, Refaat Hegazi, Kaili He, Mark Babyatsky¶, Anthony J. Bauer, and Scott E. Plevy||

From the Immunobiology Center, The Mount Sinai School of Medicine, ^¶Division of Gastroenterology, The Mount Sinai School of Medicine, New York, New York 10029 and Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Nitric oxide (NO), an important effector molecule of the innate immune system, can also regulate adaptive immunity. In this study, the molecular effects of NO on the toll-like receptor signaling pathway were determined using interleukin-12 (IL-12) as an immunologically relevant target gene. The principal conclusion of these experiments is that NO inhibits IL-1 receptor-associated kinase (IRAK) activity and attenuates the molecular interaction between tumor necrosis factor receptor-associated factor-6 and IRAK. As a consequence, the NO donor S-nitroso-N-acetylpenicillamine (SNAP) inhibits lipopolysaccharide (LPS)-induced IL-12 p40 mRNA expression, protein production, and promoter activity in murine macrophages, dendritic cells, and the murine macrophage cell line RAW 264.7. Splenocytes from inducible nitric-oxide synthase-deficient mice demonstrate markedly increased IL-12 p40 protein and mRNA expression compared with wild type splenocytes. The inhibitory action of NO on IL-12 p40 is independent of the cytokine IL-10. The effects of NO can be directly attributed to inhibition of NF-B activation through IRAK-dependent pathways. Accordingly, SNAP strongly reduces LPS-induced NF-B DNA binding to the p40 promoter and inhibits LPS-induced IB phosphorylation. Similarly, NO attenuates IL-1-induced NF-B activation. These experiments provide another example of how an innate immune molecule may have a profound effect on adaptive immunity.

Received for publication, December 8, 2003 , and in revised form, December 16, 2003.

^* 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.

^|| To whom correspondence should be addressed: Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Scaife Hall, Rm. S566, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-9573; Fax: 412-383-8913; E-mail: sep1{at}pitt.edu.

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