Recombinant interferon-gamma inhibits the mitogenic effect of platelet-derived growth factor at a level distal to the growth factor receptor.
Highly purified preparations of recombinant human interferons (rIFNs)-alpha A, -beta, and -gamma all inhibited platelet-derived growth factor (PDGF)-induced DNA synthesis in normal human dermal fibroblasts, as monitored by incorporation of [3H]-thymidine into trichloroacetic acid (TCA)-insoluble material. rIFN-gamma was the most potent, since it blocked the PDGF response by 50% at about 10 U/ml or 0.3 ng/ml, whereas with rIFN-alpha A and rIFN-beta 4000 U/ml and 600 U/ml, respectively (10 ng/ml in both cases), were required to achieve the same effect. There was a close parallelism between the ability of these rIFNs to inhibit PDGF mitogenic activity and their capacity to inhibit cell proliferation in serum-containing medium. None of the rIFNs inhibited specific binding of 125I-PDGF to fibroblasts, and none interfered with receptor internalization. The mechanism of action of rIFN-gamma was analyzed further. rIFN-gamma did not inhibit uptake of [3H]-thymidine into these cells. However, it shifted if the time point of initiation of DNA synthesis from about 14 h after stimulation with PDGF to about 18 to 21 h and decreased significantly the rate of the DNA synthesis. rIFN-gamma could be added up to 6 h following stimulation with PDGF with no loss of its inhibitory effect. rIFN-gamma also blocked the mitogenic activity of epidermal growth factor and basic fibroblast growth factor. Taken together these results implicate that rIFN-gamma exerts its antimitogenic effect by inhibiting a process that occurs late in the PDGF signaling pathway and onto which the activity pathways of other mitogens converge. In view of the important role PDGF may play in wound-healing and in the pathogenesis of the proliferative lesions of arteriosclerosis, these data point to a possible role IFN-gamma may play as a regulator of these processes in vivo.
Hosang
M
M
F. Hoffmann-La Roche & Co., Ltd., Pharmaceutical Research Department, Basel, Switzerland.
D002455:Cell Division; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis*; D005347:Fibroblasts; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007399:Interphase; D007700:Kinetics; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor; D011994:Recombinant Proteins / Q000494:pharmacology
D007370:Interferon Type I; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D007371:Interferon-gamma; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor