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

Details

• Personal Author:
  Castranova, Vincent ; Hah JS ; Kang JL ; Porter, Dale
• 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 Environmental Monitoring Laboratories Occupational Health Respiratory System Safety Silicon Dioxide
• Keywords:
  Animal-studies Dose-response Exposure-assessment Exposure-levels Inhalation-studies Laboratory-animals Silica-dusts Silicates Silicosis
• ISSN:
  0892-6638
• Document Type:
  Text
• Genre:
  Abstract or Summary ; Proceedings
• Place as Subject:
  District of Columbia ; 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:
  13
• Issue:
  4
• NIOSHTIC Number:
  nn:20030688
• Citation:
  FASEB J 1999 Mar; 13(4)(Pt 1):A505
• CAS Registry Number:
  Quartz (SiO2) (CAS RN 14808-60-7) ; Silica (CAS RN 7631-86-9)
• Federal Fiscal Year:
  1999
• Peer Reviewed:
  False
• Part Number:
  1
• Source Full Name:
  The FASEB Journal
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:58d0b13fc64a53e81eafe4354dbf73d567a3f9bbd9dcf44c8c5530971dda32867df92a8256923458f1ea284f0fa3cb5017cef7c16843133c6682b883a0f268dc
• Download URL:
  https://stacks.cdc.gov/view/cdc/191216/cdc_191216_DS1.pdf
• File Type:
  [PDF - 350.35 KB ]