Nitric oxide up-regulates DNA-binding activity of nuclear factor-κB in macrophages stimulated with silica and inflammatory stimulants

Jihee Lee Kang1, Kyungeun Lee2, Vincent Castranova3
1Department of Physiology, College of Medicine, Division of Cell Biology, Ewha Medical Research Center and Center for Cell Signaling Research, Ewha Womans University, Seoul, Korea
2Department of Pharmacology, College of Medicine, Division of Cell Biology, Ewha Medical Research Center and Center for Cell Signaling Research, Ewha Womans University, Seoul, Korea
3Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, USA

Tóm tắt

Nitric oxide (NO), a reactive nitrogen species, plays an important role in inflammatory lung damage. In the present study, we investigated the role of NO in DNA-binding activity of NF-κB in macrophages stimulated with silica or other inflammatory stimulants. Treatment of mouse macrophages (RAW264.7 cells) with a selective inhibitor of inducible nitric oxide synthase (iNOS), L-N6-(1-iminoethyl) lysine (L-NIL), or a nonselective iNOS inhibitor, Nω-nitro-L-arginine methylester (L-NAME), resulted in inhibition of silica-induced nitric oxide production as well as silica-induced NF-κB activation. L-NIL also effectively inhibited NF-κB activation induced by other inflammatory stimulants, such as lipopolysaccharide (LPS) or muramyl dipeptide (MDP). These inhibitory effects of L-NIL and L-NAME on silica- or LPS-induced NF-κB activation were also observed in primary rat alveolar macrophages. Furthermore, NO generating compounds, such as sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), caused a dose-dependent increase in NF-κB activation, which was positively correlated with the level of NO production. Specific inhibitors of protein tyrosine kinase, such as genistein and AG494, prevented NF-κB activation in SNP- or SIN-1 treated cells, suggesting involvement of tyrosine kinase in the NO signaling pathway leading to NF-κB activation. In contrast, inhibitors of protein kinase C or A, such as staurosporine or H89, had no inhibitory effect on SIN-1 induced NF-κB activation. Metalloporphyrins, such as tetrakis (N-methyl-4′-pyridyl) porphyrinato iron (III) (Fe-TMPyP) and Zn-TMPyP which are known to alter NO-dependent activity, markedly inhibited silica- and LPS-induced NF-κB activation. The results suggest that NF-κB activation in macrophages can be induced under certain conditions by nitric oxide and that nitric oxide produced by phagocytes exposed to inflammatory agents may up-regulate the activation of NF-κB.

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