EFFECTS OF EXOGENOUS IL-1-BETA, TNF-ALPHA, IL-6, IL-8 AND LIF ON CYTOKINE PRODUCTION BY HUMAN ARTICULAR CHONDROCYTES

Cytokines are potent regulators of the chondrocyte functions. Some of them are produced by chondrocytes and interact to regulate cartilage m etabolism. In this study, we investigated the production of interleuki n-1 beta (IL-1 beta), IL-6, IL-8 and leukemia inhibitory factor (LIF) by human chondrocytes and examined the modulation of their secretion b y exogenous cytokines. Human articular chondrocytes were isolated from their extracellular matrix by a triple successive enzymatic digestion of the cartilage. Subsequently, chondrocytes were stimulated by incre ased amounts of human recombinant cytokines [IL-1 beta, tumour necrosi s factor alpha (TNF alpha), IL-8, LIF, IL-6]. IL-1 beta, IL-6, IL-8 an d LIF were assayed into culture media and inside cell extracts by spec ific enzyme amplified sensitivity immunoassays (EASIAs). Under these e xperimental conditions, we have identified various interactions betwee n cytokines. IL-P and TNF alpha highly stimulated IL-6, LIF and IL-8 p roductions. IL-6 decreased IL-8 synthesis and increased LIF production . IL-8 slightly enhanced IL-6 production. Finally, LIF stimulated IL-1 beta, IL-6 and IL-8 productions. Using neutralizing antibodies agains t IL-1, we demonstrated that the effects of LIF were secondary to the stimulation by LIF of IL-1 beta production by the chondrocytes. In con clusion, chondrocytes secrete a variety of immunocompetent cytokines i ncluding IL-1 beta, IL-6, IL-8 and LIF that can interact to regulate c hondrocytes metabolism. These results also define new biological activ ities of LIF and IL-6, and raise questions concerning their role in th e pathogenesis of joint diseases.