CYTOKINE REGULATION OF PROTEOGLYCAN PRODUCTION IN FIBROBLASTS - SEPARATE AND SYNERGISTIC EFFECTS

We have studied the effects of cytokines, separately or in combination , on the production of proteoglycans in confluent cultures of fibrobla sts. The cytokines used were the transforming growth factor-beta (TGF- beta), the platelet derived growth factor-AA (PDGF-AA), the platelet d erived growth factor-BB (PDGF-BB) and the epidermal growth factor (EGF ). Hyaluronan production increased in cells treated with TGF-beta, PDG F-AA and PDGF-BB. Combining pairs of factors did not contribute furthe r to hyaluronan production, whereas the triple combination of EGF, TGF -beta and PDGF-BB induced an additional 1.9-fold increase. Proteoglyca n production was only increased by TGF-beta alone. As for hyaluronan, combining pairs of the cytokines had no further effect on metabolism, whereas the combination of EGF, TGF-beta and PDGF-BB induced a further 1.6-fold increase in production and secretion. Compared with the cont rol, an extensive increase in proteoglycan production was generated by the combination of EGF, TGF-beta and PDGF-BB, 7-fold for biglycan, ap proximately 5-fold for versican and hyaluronan and 2.4-4-fold for hepa ran sulfate proteoglycan and decorin. Compared with TGF-beta alone, th is combination increased, in falling order, the production of heparan sulfate proteoglycan, hyaluronan, biglycan, decorin and versican. The mRNA levels for the various proteoglycans did not completely agree wit h the changes in production, suggesting that changes not only in synth esis but also in rate of degradation generate these variations. The da ta indicate that cytokines cooperate to produce a proper and physiolog ical response, one needed by the organism during physiological and pat hophysiological remodeling.