title: Role of nitric oxide, reactive oxygen species, and p38 MAP kinase in the regulation of human chondrocyte apoptosis.
abstract: This study addresses mechanisms by which interleukin-1beta (IL-1beta) regulates human chondrocyte apoptosis induced by a combination of the anti-CD95 antibody CH-11 and the proteasome inhibitor (PSI). The effect of IL-1beta on apoptosis varied among tissue samples. IL-1beta either enhanced (16/22 samples) or inhibited (6/22 samples) DNA fragmentation and caspase-3 processing. The protective effect of IL-1beta was abrogated by the nitric oxide (NO) synthesis inhibitor N-monomethyl-l-arginine (L-NMMA) while apoptosis stimulation was not affected. The NO-donors sodium nitroprusside (SNP) and S-nitroso-N-acetyl penicillamine (SNAP) blocked DNA fragmentation, and this was associated with partial inhibition of caspase-3 processing. Pyrrolidine dithiocarbamate (PDTC), a scavenger of reactive oxygen species (ROS) blocked apoptosis induction by CH-11/PSI as well as the enhancement by IL-1beta. The pro-apoptotic effects of IL-1beta were also abrogated by the p38 inhibitor SB 202190. In conclusion, IL-1beta augments CH-11/PSI induced apoptosis in the majority of chondrocyte samples. The pro-apoptotic effect of IL-1beta is not dependent on NO. In contrast, the anti-apoptotic effect of IL-1beta observed in a minority of samples is partially NO-dependent.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kühn
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shikhman
authors.forename: Martin
authors.initials: M
authors.lastname: Lotz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010003:Osteoarthritis / Q000201:enzymology / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007375:Interleukin-1; D020030:Nitric Oxide Donors; C121623:PSMF1 protein, human; D011506:Proteins; D017382:Reactive Oxygen Species; D019014:fas Receptor; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex