Recombinant interferon‐γ inhibits the mitogenic effect of platelet‐derived growth factor at a level distal to the growth factor receptor

Abstract

Highly purified preparations of recombinant human interferons (rIFNs)‐αA, ‐β, and ‐γ 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‐γ 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‐αA and rIFN‐β 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‐γ was analyzed further. rIFN‐γ 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‐γ could be added up to 6 h following stimulation with PDGF with no loss of its inhibitory effect. rIFN‐γ also blocked the mitogenic activity of epidermal growth factor and basic fibroblast growth factor. Taken together these results implicate that rIFN‐γ 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‐γ may play as a regulator of these processes in vivo.