Cooperativity Between Oxidants and Tumor Necrosis Factor in the Activation of Nuclear Factor (NF)-kappaB: Requirement of Ras/Mitogen-Activated Protein Kinases in the Activation of NF-kappaB by Oxidants

Details

• Personal Author:
  Janssen-Heininger YM ; Macara I ; Mossman BT
• Description:
  The transcription factor nuclear factor (NF)-kappaB is activated by oxidative stress or cytokines and is critical to the activation of inflammatory genes. Here, we report that hydrogen peroxide or 3-morpholinosydnonimine, which simultaneously releases nitric oxide and superoxide, synergize with the cytokine tumor necrosis factor (TNF)-alpha to activate NF-kappaB in rat lung epithelial cells, suggesting that signaling pathways elicited by reactive oxygen species (ROS)/reactive nitrogen species (RNS) are different from TNF-induced signaling. These findings were substantiated by observations that levels of IkappaB-alpha did not change after exposure to ROS/RNS, whereas a rapid depletion of IkappaB-alpha was observed in cells exposed to TNF. In addition, the proteosome inhibitor MG132 did not affect activation of NF-kappaB by ROS/RNS, whereas it abolished the TNF response. Transfection of a dominant negative Ras construct prevented the activation of NF-kappaB by ROS/RNS, demonstrating the requirement for Ras in the activation of NF-kappaB by oxidants. In contrast, TNF activated NF-kappaB in a Ras-independent fashion. Evaluation of members of the mitogen-activated protein kinase (MAPK) family as downstream effectors of Ras revealed the requirement of MAPK/ extracellular-regulated kinase (ERK) kinase kinase (MEKK)1 and c-Jun N-terminal kinases in the induction of NF-kappaB by both oxidants and TNF, whereas the MEK-ERK pathway negatively regulates NF-kappaB. Our findings demonstrate that cytokines and oxidants cooperate in the activation of transcription factors through distinct pathways, and suggest that anti-inflammatory and antioxidant therapies may be required in concert to prevent the activation of NF-kappaB-regulated genes important in the development of inflammatory diseases. [Description provided by NIOSH]
• Subjects:
  Immune System Lung Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Bioactivation Immunochemistry Inhalation-studies Lung-cells Nucleic-acids Proteins Pulmonary-system-disorders
• ISSN:
  1044-1549
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 1 ; Vermont
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  20
• Issue:
  5
• NIOSHTIC Number:
  nn:20030046
• Citation:
  Am J Respir Cell Mol Biol 1999 May; 20(5):942-952
• Contact Point Address:
  Yvonne M. W. Janssen-Heininger, Ph.D., Dept. of Pathology, University of Vermont, Medical Alumni Bldg., A-143, Burlington, VT 05405
• Email:
  yjanssen@zoo.uvm.edu
• CAS Registry Number:
  Asbestos (CAS RN 1332-21-4) ; Chrysotile (CAS RN 12001-29-5) ; Crocidolite asbestos (CAS RN 12001-28-4)
• Federal Fiscal Year:
  1999
• Performing Organization:
  Pathology University of Vermont Medical Alumni Bldg a 249 Burlington, VT 05405-0068
• Peer Reviewed:
  True
• Start Date:
  19970401
• Source Full Name:
  American Journal of Respiratory Cell and Molecular Biology
• End Date:
  20000331
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:27590fc3ee06fd30d91f7b4dcb1214f71678fa6ee99fab4e8b49b186144201b06d72eef4bddf8240685f6fcddfb4b77180b505adf67b2491f58e58de1e388f1d
• Download URL:
  https://stacks.cdc.gov/view/cdc/190898/cdc_190898_DS1.pdf
• File Type:
  [PDF - 513.52 KB ]