CYTOKINE MODULATION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 (PAI-1) PRODUCTION BY HUMAN ARTICULAR-CARTILAGE AND CHONDROCYTES - DOWN-REGULATIONBY TUMOR-NECROSIS-FACTOR-ALPHA AND UP-REGULATION BY TRANSFORMING GROWTH-FACTOR-BETA AND BASIC FIBROBLAST GROWTH-FACTOR

Recombinant human cytokines were examined for their effects on plasmin ogen activator inhibitor-1 (PAI-1) production by human articular carti lage and chondrocyte monolayer cultures. Cartilage and chondrocytes we re cultured with and without added cytokines and the conditioned media assayed for PAI-1 by a specific enzyme-linked immunosorbent assay, an d mRNA levels determined by Northern blot analysis. Tumor necrosis fac tor alpha (TNF alpha) reduced, and transforming growth factor-beta (TG F-beta) and basic fibroblast growth factor (bFGF) increased, the level s of PAI-1 antigen and mRNA in the culture fluids and cell extracts, r espectively. The effects of TNF alpha and TGF-beta on PAI-1 antigen le vels were both time- and concentration-dependent; optimum doses being 10-100 pM TNF alpha and 0.4-0.8 nM TGF-beta, with each cytokine exerti ng its effect on PAI-1 antigen levels within 8 h of addition to cultur e. TNF alpha (and interleukin-1 alpha) also countered the effects of T GF-beta and bFGF. The anti-inflammatory drugs, indomethacin and dexame thasone, did not appear to modulate PAI-1 levels in cultures of cartil age tissue. The inhibition of PAI-1 levels by cytokines and reagents w hich stimulate cartilage resorption (i.e., TNF(alpha, interleukin-1 al pha, retinoic acid) and enhancement by cytokines which counter it (i.e ., TGF-beta, bFGF) further implicate plasminogen activator in the mech anism(s) of cartilage degradation in diseases such as arthritis.