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

Authors
Kang-JL; Castranova-V
Source
FASEB J 2000 Mar; 14(4):A193
NIOSHTIC No.
20025888
Abstract
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-kappaB 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, N omega-nitro-L-arginine methylester (L-NAME), resulted in inhibition of silica-induced nitric oxide production as well as silica-induced NF-kappaB activation. L-NIL also effectively inhibited NF-kappaB 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-kappaB 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-kappaB activation, which was positively correlated with the level of NO production. Specific inhibitors of protein tyrosine kinase, such as genistein and AG494, prevented NF-kappaB activation in SNP- or SIN-1 treated cells, suggesting involvement of tyrosine kinase in the NO signaling pathway leading to NF-kappaB activation. In contrast, inhibitors of protein kinase C or A, such as staurosporine or H89, had no inhibitory effect on SIN-1 induced NF-kappaB 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-kappaB activation. The results suggest that NF-kappaB 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-kappaB. The inhibitory effects of L-NIL and L-NAME on silica- or LPS-induced NF-kB 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-kB activation which was positively correlated with the level of NO production. Specific inhibitors of protein tyrosine kinase, such as genistein and AG494, prevented NF-kB activation in SNP- or SIN-1 treated cells, suggesting involvement of tyrosine kinase in the NO signaling pathway leading to NF-kB activation. In contrast, inhibitors of protein kinase C or A, such as staurosporine, or H89, had no inhibitory effect on SIN-1-induced NF-kB activation. The results suggest that NF-kB activation in macrophages induced by silica or other inflammatory stimulants is partially up-regulated by nitric oxide produced by these phagocytes.
Keywords
Stimulants; Silica-dusts; Silicates; Lung-disorders; Pulmonary-system-disorders; Respiratory-system-disorders; Phagocytes; Laboratory-animals; Animals; Animal-studies
CODEN
FAJOEC
CAS No.
10102-43-9
Publication Date
20000315
Document Type
Abstract; Conference/Symposia Proceedings
Fiscal Year
2000
NTIS Accession No.
NTIS Price
Issue of Publication
4
ISSN
0892-6638
NIOSH Division
HELD
Source Name
The FASEB Journal
State
WV
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