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-1 beta and IL-6 on expression of TGF-beta isoforms in human articular chondrocytes. IL-6 caused a fivefold increase, in the secretion of TGF-beta bioactivity by primary chondrocytes, whereas IL-1 beta showed only marginal stimulatory effects. Analysis by Northern blotting showed that IL-6 induced TGF-beta 1 gene expression but had no detectable effect on TGF-beta 2 mRNA levels and marginally increased TGF-beta 3 mRNA. However, IL-1 inhibited TGF-beta 1 mRNA expression induced by serum. In contrast, IL-1 beta strongly and selectively upregulated the TGF-beta 3 isoform. To determine whether this differential effect of IL-1 beta resulted in a corresponding change in protein synthesis, chondrocytes were metabolically labeled and analyzed by immunoprecipitation. IL-1 beta selectively induced TGF-beta 3 protein synthesis but reduced synthesis of the TGF-beta 1 and TGF-beta 2 isoforms. Consistent with the effects on TGF-beta 1 mRNA, IL-6 increased the synthesis of TGF-beta 1. These differential effects of the cytokines IL-1 beta and IL-6 provide new insight into the regulation of TGF-beta expression and may represent a protective mechanism against cytokine-induced connective tissue catabolism.