Cytokine modulation of plasminogen activator inhibitor-1 (PAI-1) production by human articular cartilage and chondrocytes. Down-regulation by tumor necrosis factor α and up-regulation by transforming growth factor-β and basic fibroblast growth factor

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Abstract

Recombinant human cytokines were examined for their effects on plasminogen activator inhibitor-1 (PAI-1) production by human articular cartilage and chondrocyte monolayer cultures. Cartilage and chondrocytes were cultured with and without added cytokines and the conditioned media assayed for PAI-1 by a specific enzyme-linked immunosorbent assay, and mRNA levels determined by Northern blot analysis. Tumor necrosis factor α (TNFα) reduced, and transforming growth factor-β (TGF-β) and basic fibroblast growth factor (bFGF) increased, the levels of PAI-1 antigen and mRNA in the culture fluids and cell extracts, respectively. The effects of TNFα and TGF-β on PAI-1 antigen levels were both time- and concentration-dependent; optimum doses doing 10–100 pM TNFα and 0.4–0.8 nM TGF-β, with each cytokine exerting its effect on PAI-1 antigen levels within 8 h of addition to culture. TNFα (and interleukin-1α) also countered the effects of TGF-β and bFGF. The anti-inflammatory drugs, indomethacin and dexamethasone, did not appear to modulate PAI-1 levels in cultures of cartilage tissue. The inhibition of PAI-1 levels by cytokines and reagents which stimulate cartilage resorption (i.e., TNFα, interleukin-1α, retinoic acid) and enhancement by cytokines which counter it (i.e., TGF-β, bFGF) further implicate plasminogen activator in the mechanism(s) of cartilage degradation in diseases such as arthritis.

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      Members of the ADAMTS family are known to be involved in proteoglycan cleavage. Many in vitro experiments with tissue or cells point to a role for the plasminogen–plasmin system in the activation of proMMPs.11,35 IL-1 and TNFα-induced proteoglycan release can be blocked with an inhibitor of the urokinase-type plasminogen activator (uPA).36

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    Present address: Laboratory for Clinical-Experimental Physiology, Department of Medical Physiology, University of Vienna, Vienna, Austria.

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