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 fibroblasts. The cytokines used were the transforming growth factor-beta (TGF-beta), the platelet derived growth factor-AA (PDGF-AA), the platelet derived growth factor-BB (PDGF-BB) and the epidermal growth factor (EGF). Hyaluronan production increased in cells treated with TGF-beta, PDGF-AA and PDGF-BB. Combining pairs of factors did not contribute further to hyaluronan production, whereas the triple combination of EGF, TGF-beta and PDGF-BB induced an additional 1.9-fold increase. Proteoglycan 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 control, an extensive increase in proteoglycan production was generated by the combination of EGF, TGF-beta and PDGF-BB, 7-fold for biglycan, approximately 5-fold for versican and hyaluronan and 2.4-4-fold for heparan sulfate proteoglycan and decorin. Compared with TGF-beta alone, this 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 with the changes in production, suggesting that changes not only in synthesis but also in rate of degradation generate these variations. The data indicate that cytokines cooperate to produce a proper and physiological response, one needed by the organism during physiological and pathophysiological remodeling.