SYNERGISTIC INTERACTION OF INTERLEUKIN-1-BETA AND GROWTH-FACTORS IN PRIMARY CULTURES OF RAT AORTIC SMOOTH-MUSCLE CELLS

Activated macrophages release cytokines and growth factors that may contribute to the growth of vascular smooth muscle cells in injured blood vessels. In the present study, we investigated the interactions between interleukin-1 beta (IL-1 beta) and basic fibroblast growth factor (FGF-2) in primary rat aortic smooth muscle cells, relative to their effects on DNA synthesis and cell proliferation. We report that femtomolar levels of IL-1 beta, which alone were non-mitogenic or weakly mitogenic, synergistically increased FGF-2-induced [H-3]thymidine incorporation and cell proliferation. The potentiating effect of IL-1 beta extended to PDGF-AB and EGF, but not to IGF-1-induced thymidine incorporation. An antagonist of the IL-1 receptor, IL-1ra, blocked the co-mitogenic effect of IL-1 beta. Stimulation of cells with FGF-2 and IL-1 beta increased both DNA content and proliferation, an observation that was consistent with the thymidine incorporation experiments. An inhibitor of NO synthase, N-5-iminoethyl L-ornithine (L-NlO), did not block the co-mitogenic effect of IL-1 beta, despite effective inhibition of NO synthase activity, suggesting that the synergistic interaction between IL-1 beta and FGF-2 was independent of the NO/cGMP pathway. The mechanism of co-mitogenesis appeared to be independent of the intermediacy of PDGF-AA, IL-6, and prostanoids, and was not associated with increased levels of c-fos mRNA, FGF receptor-1 protein, or FGF-2-induced early and delayed tyrosine phosphorylation events. We conclude that IL-1 beta interacts with FGF-2 to amplify the proliferation of primary rat aortic smooth muscle cells, an effect that may be important in vascular smooth muscle cell proliferation following vascular injury. (C) 1995 Wiley-Liss, Inc.