Divergent stress responses to IL-1β, nitric oxide, and tunicamycin by chondrocytes

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-1 beta, 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-28/12, were treated with IL-1 beta, 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-1 beta treatment induced PERK and eIF2-alpha phosphorylation, but not GADD153 expression or apoptosis. The ER stress signaling pathway of IL-1 beta 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-1 beta, 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.