Silica-Induced Nuclear Factor-kappaB Activation: Involvement of Reactive Oxygen Species and Protein Tyrosine Kinase Activation

Details

• Personal Author:
  Castranova, Vincent ; Go YH ; Hur KC ; Kang JL
• Description:
  Nuclear factor-kappaB (NF-kappaB) is a multiprotein complex that may regulate a variety of inflammatory cytokines involved in the initiation and progression of silicosis. The present study documents the ability of in vitro silica exposure to induce DNA-binding activity of NF-kappaB in a mouse peritoneal macrophage cell line (RAW264.7 cells) and investigates the role of reactive oxygen species (ROS) and/or protein tyrosine kinase in this activation. In vitro exposure of mouse macrophages to silica (100 microg/ml) resulted in a twofold increase in ROS production, measured as the generation of chemiluminescence (CL), and caused activation of NF-kappaB. Silica-induced CL was inhibited 100% by superoxide dismutase (SOD) and 75% by catalase, while NF-kappaB activation was inhibited by a variety of antioxidants (catalase, superoxide dismutase, alpha-tocopherol, pyrrolidine dithiocarbamate, or N-acetylcysteine). Further evidence for the involvement of ROS in NF-kappaB activation is that 1 mM H2O2 enhanced NF-kappaB/DNA binding and that this activation was inhibited by catalase. Specific inhibitors of protein tyrosine kinase, such as herbimycin A, genistein, and AG-494, prevented NF-kappaB activation in silica-treated cells. Genistein and AG-494 also reduced NF-kappaB activation in H2O2-treated cells. Results confirm that tyrosine phosphorylation of several cellular proteins (approximate molecular mass of 39, 58-70, and 103 kD) was increased in silica-exposed macrophages and that genistein inhibited this silica-induced phosphorylation. In contrast, inhibitors of protein kinase A or C, such as H89, staurosporin, calphostin C, and H7, had no marked inhibitory effect on silica-induced NF-kappaB activation. The results suggest that ROS may play a role in silica-induced NF-kappaB activation in macrophages and that phosphorylation events mediated by tyrosine kinase may be involved in this activation. [Description provided by NIOSH]
• Subjects:
  Aluminum Silicates Animals Antioxidants Laboratories Occupational Health Safety Silicon Dioxide
• Keywords:
  Animal Studies Exposure Assessment In Vitro Studies Laboratory Animals Silica Dusts Silicates Silicosis
• ISSN:
  1528-7394
• Document Type:
  Text
• Genre:
  Journal Article
• 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
• Pages in Document:
  27-46
• Volume:
  60
• Issue:
  1
• NIOSHTIC Number:
  nn:20020715
• Citation:
  J Toxicol Environ Health A 2000 May; 60(1):27-46
• Contact Point Address:
  Jihee Lee Kang, MD, PhD, Department of Physiology, College of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-ku, Seoul 158-056, Korea
• Email:
  jihee@mm.ewha.ac.kr
• CAS Registry Number:
  L-Tyrosine (CAS RN 55520-40-6) ; Silica (CAS RN 7631-86-9)
• Federal Fiscal Year:
  2000
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Toxicology and Environmental Health, Part A: Current Issues
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:f5963010945e9af1af8016f8d91b28351fa4cfd502ae2f012a1d041e457833cebb1f5296a435cdb34e26d695b4250a7cba6cb73734e4e6e905a6d8848951c9c9
• Download URL:
  https://stacks.cdc.gov/view/cdc/198391/cdc_198391_DS1.pdf
• File Type:
  [PDF - 377.01 KB ]