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 approximately 28 h after addition of TNF-alpha to quiescent fibroblasts, a delay of about 12 to 14 h as compared with DNA synthesis elicited by platelet-derived growth factor (PDGF). TNF-alpha induces PDGF A chain 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 goat 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-receptor mRNA or protein expression, nor does it alter the proliferative response to externally added PDGF-AA. In contrast, TNF-alpha reduces the levels of PDGF beta-receptor mRNA, protein expression, and cell proliferation in response to PDGF-BB. Thus, DNA synthesis in response to TNF-alpha depends upon autocrinely induced PDGF-AA. At the same time, TNF-alpha may alter the response to PDGF-BB from exogenous sources.
Battegay
E J
EJ
Department of Research, University Hospital, Basel, Switzerland.
Raines
E W
EW
Colbert
T
T
Ross
R
R
D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000276:immunology; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007106:Immune Sera; D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D017479:Receptors, Platelet-Derived Growth Factor