p38 map kinase regulates TNF-alpha production in human astrocytes and microglia by multiple mechanisms.
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.
Lee
Y B
YB
Division of Neurology, University of British Columbia, Vancouver, Canada.
Schrader
J W
JW
Kim
S U
SU
D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580