TNF-ALPHA STIMULATION OF FIBROBLAST PROLIFERATION - DEPENDENCE ON PLATELET-DERIVED GROWTH-FACTOR (PDGF) SECRETION AND ALTERATION OF PDGF RECEPTOR EXPRESSION

TNF-alpha stimulates DNA synthesis and proliferation of cultured human fibroblasts. Maximal DNA synthesis in response to TNF-alpha occurs ap proximately 28 h after addition of TNF-alpha to quiescent fibroblasts, a delay of about 12 to 14 h as compared with DNA synthesis elicited b y platelet-derived growth factor (PDGF). TNF-alpha induces PDGF A chai n gene expression with a maximum at 4 h. DNA synthesis is abrogated in response to TNF-alpha by a goat anti-PDGF IgG but not by nonimmune go at IgG, suggesting induction of an autocrine PDGF-AA loop by TNF-alpha . The response to PDGF-AA requires the presence of PDGF receptor alpha -receptors. TNF-alpha does not significantly affect PDGF alpha-recepto r mRNA or protein expression, nor does it alter the proliferative resp onse to externally added PDGF-AA. in contrast, TNF-alpha reduces the l evels of PDGF beta-receptor mRNA, protein expression, and cell prolife ration in response to PDGF-BB. Thus, DNA synthesis in response to TNF- alpha depends upon autocrinely induced PDGF-AA. Al the same time, TNF- alpha may alter the response to PDGF-BB from exogenous sources.