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-κB activation through IRAK-dependent pathways. Accordingly, SNAP strongly reduces LPS-induced NF-κB DNA binding to the p40 promoter and inhibits LPS-induced IκB phosphorylation. Similarly, NO attenuates IL-1β-induced NF-κB activation. These experiments provide another example of how an innate immune molecule may have a profound effect on adaptive immunity.
CITATION STYLE
Xiong, H., Zhu, C., Li, F., Hegazi, R., He, K., Babyatsky, M., … Plevy, S. E. (2004). Inhibition of Interleukin-12 p40 Transcription and NF-κB Activation by Nitric Oxide in Murine Macrophages and Dendritic Cells. Journal of Biological Chemistry, 279(11), 10776–10783. https://doi.org/10.1074/jbc.M313416200
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