p38 map kinase regulates TNF-alpha production in human astrocytes and microglia by multiple mechanisms

Cytokine. 2000 Jul;12(7):874-80. doi: 10.1006/cyto.2000.0688.


In the vertebrate central nervous system (CNS), tumour necrosis factor-alpha (TNF-alpha) is produced by astrocytes and microglia and mediates cell injury in nerve cells and oligodendrocytes. In the present study, we have used a specific inhibitor of p38 MAP kinase, SB203580 to examine the role of p38 MAP kinase in regulation of TNF-alpha production in human astrocytes and microglia in terms of levels of mRNA and secreted protein. A reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed that increased levels of TNF-alpha mRNA were induced in astrocytes by IL-1beta treatment, and in microglia by bacterial lipopolysaccharide (LPS). In microglia, treatment with SB203580 reduced the level of TNF-alpha mRNA, but in astrocytes it did not. However, the secretion of TNF-alpha by both astrocytes and microglia was markedly inhibited by SB203580 at a low concentration. TNF-alpha secretion was reduced approximately 80% in astrocytes and 85% in microglia. The results demonstrate a key role played by p38 MAP kinase in upregulation of TNF-alpha mRNA levels in LPS-activated human microglia, whereas p38 MAP kinase is involved in post-transcriptional regulation of TNF-alpha production at translational level in IL-1beta-activated human astrocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-1 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Microglia / cytology
  • Microglia / drug effects
  • Microglia / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Pyridines / pharmacology
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / genetics
  • p38 Mitogen-Activated Protein Kinases


  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-1
  • Lipopolysaccharides
  • Pyridines
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580