title: Modulation of human microglia and THP-1 cell toxicity by cytokines endogenous to the nervous system.
abstract: Neuroinflammatory processes are thought to be a significant factor in the pathology of a number of degenerative neurological diseases. A variety of cytokines influence inflammatory levels. Here we show that a cooperative action of two or more cytokines is required to induce significantly human microglial and monocytic THP-1 cell toxicity towards SH-SY5Y neuroblastoma cells. Such toxicity was induced by the following combinations: interferon-gamma (IFN-gamma) with tumor necrosis factor-alpha (TNF-alpha); IFN-gamma with interleukin (IL) 1alpha or IL-1beta in the presence of TNF-alpha; and IL-6 with TNF-alpha. Toxicity induced by the various stimulatory combinations was not accompanied by an increased nitrite production. Of the potential inhibitors tested, IL-4 downregulated the toxic action of microglia when applied to THP-1 cells either before stimulation or 24 h after stimulation. Toxicity was not inhibited by IL-10, and was even enhanced by transforming growth factor-beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF). These data suggest that antagonists of cytokine receptors, as well as inhibitors of their intracellular pathways may be effective anti-inflammatory agents.
authors.affiliation: Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Andis
authors.initials: A
authors.lastname: Klegeris
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bissonnette
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
mesh_terms: D000704:Analysis of Variance; D002452:Cell Count / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D017628:Microglia / Q000166:cytology* / Q000187:drug effects; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects; D009447:Neuroblastoma; D009573:Nitrites / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013702:Temporal Lobe / Q000166:cytology; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
chemical_list: D003470:Culture Media; D016207:Cytokines; D008070:Lipopolysaccharides; D009573:Nitrites; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue