Silica Induces Nuclear Factor-B Activation Through Tyrosine Phosphorylation of 1kB-X in RAW264.7 Macrophages

Details

• Personal Author:
  Castranova, Vincent ; Hong SM ; Kang JL ; Lee HS ; Pack IS
• Description:
  It was previously reported that protein tyrosine kinase (PTK) but not protein kinase C or A plays an important role in silica-induced activation of NF-kB in macrophages. The question is raised whether PTK stimulation and NF-kB activation in silica-stimulated macrophages are directly connected through tyrosine phosphorylation of IkB-a. Results indicate that stimulation of macrophages with silica led to NF-kB activation through tyrosine phosphorylation without serine phosphorylation. Specific inhibitors of protein tyrosine kinase, such as genistein and tyrophostin AG126, prevented tyrosine phosphorylation of IkB-a in response to silica. IkB-a protein levels remained relatively unchanged for up to 60 min after silica stimulation. Moreover, inhibition of proteasome proteolytic activity did not affect NF-kB activation by silica. Antioxidants, such as superoxide dismutase (SOD), N-acetylcysteine (NAC), and pyrrolidine dithiocarbamate (PDTC), blocked tyrosine phosphorylation of IkB-a induced by silica, suggesting reactive oxygen species (ROS) may be important regulatory molecules in NF-kB activation through tyrosine phosphorylation of IkB-a. The results suggest that tyrosine phosphorylation of IkB-a represents a proteasome proteolytic activity-independent mechanism for NF-kB activation that directly couples NF-kB to cellular tyrosine kinase in silica-stimulated macrophages. This proposed mechanism of NF-kB activation induced by silica could be used as a target for development of antiinflammatory and antifibrosis drugs. [Description provided by NIOSH]
• Subjects:
  Aluminum Silicates Antioxidants Lung Lung Diseases Occupational Health Respiratory System Respiratory Tract Diseases Safety Silicon Dioxide
• Keywords:
  Author Keywords: Silica IkB-a Lung Disorders Lung Fibrosis Macrophages NF-kB Pulmonary System Disorders Reactive Oxygen Species Respiratory System Disorders Silica Dusts Silicates Silicosis Tyrosine Phosphorylation

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• ISSN:
  0041-008X
• 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:
  59-65
• Volume:
  169
• Issue:
  1
• NIOSHTIC Number:
  nn:20020717
• Citation:
  Toxicol Appl Pharmacol 2000 Nov; 169(1):59-65
• Email:
  jihee@mm.ewha.ac.kr
• CAS Registry Number:
  L-Tyrosine (CAS RN 55520-40-6)
• Federal Fiscal Year:
  2001
• Peer Reviewed:
  True
• Source Full Name:
  Toxicology and Applied Pharmacology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:f05f5a0399fa9d9d9be61e1d00fede8b45bdec4a7e1c0fffcf8920331df546f8e00c104a486f38a1f9fe2314be57db86cb1b180d96f46679af2c817215bc4604
• Download URL:
  https://stacks.cdc.gov/view/cdc/198393/cdc_198393_DS1.pdf
• File Type:
  [PDF - 195.94 KB ]