IL-1-BETA AND IL-6 SELECTIVELY INDUCE TRANSFORMING GROWTH-FACTOR-BETAISOFORMS IN HUMAN ARTICULAR CHONDROCYTES

Transforming growth factor-beta (TGF-beta) plays an important role in homeostasis of connective tissues, but regulation of its expression in mesenchymal cells is not well characterized. This study examines the effects of the cytokines IL-1beta and IL-6 on expression of TGF-beta i soforms in human articular chondrocytes. IL-6 caused a fivefold increa se, in the secretion of TGF-beta bioactivity by primary chondrocytes, whereas IL-1beta showed only marginal stimulatory effects. Analysis by Northern blotting showed that IL-6 induced TGF-beta1 gene expression but had no detectable effect on TGF-beta2 mRNA levels and marginally i ncreased TGF-beta3 mRNA. However, IL-1 inhibited TGF-beta1 mRNA expres sion induced by serum. In contrast, IL-1beta strongly and selectively upregulated the TGF-beta3 isoform. To determine whether this different ial effect of IL-1beta resulted in a corresponding change in protein s ynthesis, chondrocytes were metabolically labeled and analyzed by immu noprecipitation. IL-1beta selectively induced TGF-beta3 protein synthe sis but reduced synthesis of the TGF-beta1 and TGF-beta2 isoforms. Con sistent with the effects on TGF-beta1 mRNA, IL-6 increased the synthes is of TGF-beta1. These differential effects of the cytokines IL-1beta and IL-6 provide new insight into the regulation of TGF-beta expressio n and may represent a protective mechanism against cytokine-induced co nnective tissue catabolism.