We examined the effects of recombinant human tumor necrosis factor (TNF) on human articular cartilage and chondrocytes in culture. Both TNF alpha and TNF beta stimulated cartilage matrix breakdown during prolonged culture and elevated the levels of plasminogen activator (PA) activity in both the supernatants and cell layers of cultured chondrocytes. Characterization of the PA activities by immunochemistry and by zymography following gel electrophoresis indicated that human chondrocytes produce both urokinase-type PA and tissue-type PA in response to TNF. The addition of both interleukin-1 and TNF alpha or TNF beta to chondrocyte cultures demonstrated a synergism between these cytokines in the generation of PA activity in the culture supernatants and cell layers. Our results suggest that both activated lymphocytes and monocytes may contribute to the cartilage destruction of inflammatory arthritis through their stimulation of chondrocytes with TNF beta and TNF alpha, respectively. Since PA is the only neutral proteinase reported to be elevated in TNF-stimulated chondrocyte cultures, it could have an important role in TNF-mediated cartilage destruction.