Nitric Oxide Up-Regulates DNA-Binding Activity of Nuclear Factor-kB in Macrophages Stimulated with Silica and Inflammatory Stimulants

Details

• Personal Author:
  Castranova, Vincent ; Kang JL
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Aluminum Silicates Animals Laboratories Lung Diseases Occupational Health Respiratory Tract Diseases Safety Silicon Dioxide
• Keywords:
  Animal-studies Laboratory-animals Lung-disorders Phagocytes Pulmonary-system-disorders Respiratory-system-disorders Silica-dusts Silicates Stimulants
• ISSN:
  0892-6638
• Document Type:
  Text
• Genre:
  Abstract or Summary ; Proceedings
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  14
• Issue:
  4
• NIOSHTIC Number:
  nn:20025888
• Citation:
  FASEB J 2000 Mar; 14(4):A193
• CAS Registry Number:
  Nitric oxide (CAS RN 10102-43-9)
• Federal Fiscal Year:
  2000
• Peer Reviewed:
  False
• Source Full Name:
  The FASEB Journal
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:be3b5ff4ccc07e8ecf362ac6b622820660d329718283b4dff8ee2615050a268faca5ee716c2a539f41121643d507b0367fdc5eb9d89080de0faa094b7e26852b
• Download URL:
  https://stacks.cdc.gov/view/cdc/197076/cdc_197076_DS1.pdf
• File Type:
  [PDF - 455.57 KB ]