Pro- and anti-inflammatory cytokines regulate the ERK pathway: implication of the timing for the activation of microglial cells.
Pro-inflammatory molecules induce glial activation and the release of potentially detrimental factors capable of generating oxidative damage, such as nitric oxide (NO) and superoxide anion (O2.-). Activated glial cells (astrocytes and microglia) are associated to the inflammatory process in neurodegenerative diseases. A strong inflammatory response could escape endogenous control becoming toxic to neurons and contributing to the course of the disease. We evaluated in a hippocampal cells-microglia co-culture model, if the pro-inflammatory condition induced by lipopolysaccharide + interferon-gamma (LPS+IFN-gamma) promoted damage directly or if damage was secondary to glial activation. In addition, we explored the effect of the anti-inflammatory cytokine transforming growth factor-beta1 (TGF-beta1), and pro-inflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) on the regulation of the inflammatory response of microglia. We found that LPS+IFN-gamma-induced damage on hippocampal cultures was dependent on the presence of microglial cells. In hippocampal cultures exposed to LPS+IFN-gamma, TGF-beta1 was induced whereas in microglial cell cultures LPS+IFN-gamma induced the secretion of IL-1beta. TGF-beta1 and IL-1beta but not TNF-alpha decreased the NO production by 70-90%. PD98059, an inhibitor of MAP kinase (MEK), reduced the IFN-gamma-induced NO production by 40%. TGF-beta and IL-1beta reduced the IFN-gamma induced phosphorylation of ERK1,2 by 60% and 40%, respectively. However, the effect of IL-1beta was observed at 30 min and that of TGF-beta1 only after 24 h of exposure. We propose that acting with different timing, TGF-beta1 and IL-1beta can modulate the extracellular signal-regulated kinase ERK1,2, as a common element for different transduction pathways, regulating the amplitude and duration of glial activation in response to LPS+IFN-gamma. Cross-talk among brain cells may be key for the understanding of inflammatory mechanisms involved in pathogenesis of neurodegenerative diseases.
Saud
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Department of Neurology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago, Chile.
Herrera-Molina
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Von Bernhardi
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D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004996:Ethidium; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007375:Interleukin-1 / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007375:Interleukin-1; D009573:Nitrites; D013778:Tetrazolium Salts; C508962:Tgfb1 protein, rat; D013844:Thiazoles; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013481:Superoxides; D048049:Extracellular Signal-Regulated MAP Kinases; D004996:Ethidium; C022616:thiazolyl blue; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one