title: Divergent stress responses to IL-1beta, nitric oxide, and tunicamycin by chondrocytes.
abstract: As the only cell in cartilage responsible for matrix synthesis, the chondrocyte's viability is crucial to healthy tissue. It must tolerate stresses from both mechanical and cellular sources. This study examines the endoplasmic reticulum (ER) stress response in chondrocytes after exposure to IL-1beta, nitric oxide, or tunicamycin in order to determine whether this form of stress causes cell death. Cultures of the immortalized human juvenile costal chondrocyte cell line, C-28/I2, were treated with IL-1beta, S-nitroso-N-acetylpenicillamine (SNAP), and tunicamycin. Increasing intracellular nitric oxide levels by SNAP treatment or inhibiting protein folding in the ER lumen by tunicamycin induced the ER stress response as evidenced by increased protein and gene expression of GADD153 as well as PERK and eIF2-alpha phosphorylation, and resulted in apoptosis. IL-1beta treatment induced PERK and eIF2-alpha phosphorylation, but not GADD153 expression or apoptosis. The ER stress signaling pathway of IL-1beta involved iNOS because blocking its expression, inhibited ER stress gene expression. Therefore, inducing the ER stress response in chondrocytes results in divergent responses depending on the agent used. Even though IL-1beta, a common proinflammatory cytokine, induces the ER stress response, it is not proapoptotic to chondrocytes. On the other hand, exposure to high levels of intracellular nitric oxide induce chondrocyte apoptosis as part of the ER stress response.
authors.affiliation: Department of BioStructure and Function, School of Dental Medicine, University of Connecticut Heath Center, Farmington, Connecticut, USA. bolivar@up.uchc.edu
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Oliver
authors.forename: Chunxia G
authors.initials: CG
authors.lastname: Cronin
authors.forename: Yahui
authors.initials: Y
authors.lastname: Zhang-Benoit
authors.forename: Mary B
authors.initials: MB
authors.lastname: Goldring
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Tanzer
mesh_terms: D051701:Activating Transcription Factor 4; D053674:Aggrecans; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002461:Cell Line, Transformed; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D024043:Collagen Type II / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D037181:Lectins, C-Type; D018832:Molecular Chaperones / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D011509:Proteoglycans / Q000235:genetics; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D053674:Aggrecans; D000900:Anti-Bacterial Agents; D022762:CCAAT-Enhancer-Binding Proteins; D024043:Collagen Type II; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D016326:Extracellular Matrix Proteins; D006360:Heat-Shock Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D018832:Molecular Chaperones; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D011509:Proteoglycans; D026423:S-Nitroso-N-Acetylpenicillamine; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D014415:Tunicamycin; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C497249:DDIT3 protein, human; C496319:NOS2 protein, human