Platelet-derived growth factor suppresses and fibroblast growth factor enhances cytokine-induced production of nitric oxide by cultured smooth muscle cells. Effects on cell proliferation.

Abstract

Stimulation of thymidine incorporation by basic fibroblast growth factor or epidermal growth factor treatment of cultured quiescent smooth muscle cells (rat and human) was attenuated by the concomitant treatment with interleukin-1 beta in the presence of indomethacin. Platelet-derived growth factor-AB and -BB-induced thymidine incorporation was not inhibited by the presence of the cytokine under similar experimental conditions. Elevation of nitrite levels in the conditioned medium of cultures exposed to interleukin-1 beta correlated with the inhibition of thymidine incorporation. Platelet-derived growth factor-AB and -BB inhibited the production of nitric oxide (measured as nitrite levels in conditioned medium) by cells treated simultaneously with interleukin-1 beta and growth factor. However, platelet-derived growth factor-AA neither affected nitrite production nor thymidine incorporation by smooth muscle cells. Levels of cytokine-stimulated nitrite production by smooth muscle cells were increased synergistically by the presence of fibroblast growth factors or epidermal growth factor. The inhibition of thymidine incorporation and concomitant elevation of nitrite production was abolished in the presence of nitro-L-arginine. Cultures maintained in the presence of low levels of the cytokine for 9 days were growth-inhibited, and this was reversed when culture medium was supplemented with nitro-L-arginine. The treatment of smooth muscle cells, which were grown in coculture inserts with the cytokine to induce nitric oxide production, before their combination with other quiescent layers of cells resulted in the inhibition of thymidine incorporation by this second layer of cells regardless of the growth factor used for stimulation. Nitric oxide may act as an endogenous inhibitor of smooth muscle cell proliferation in the vessel wall, and impairment of its production may be one action of potent vascular mitogens such as platelet-derived growth factor.

Cytotoxic effect of autocrine and macrophage-derived nitric oxide on cultured rat mesangial cells

“…Results of some of these studies [16,17], by indicating that co-stimulation of mesangium with IL-1 and TNF-acts synergistically to generate large amounts of nitrite, prompted us to utilize concurrently both cytokines in our experiments. MC stimulated to proliferate with bFGF did not in our hands respond as vigorously by production of nitrite to stimulation with IL-1 and TNF-as did quiescent cells, contrary to vascular smooth muscle cells, which more remarkably enhance generation of NO 2 -upon triggering with IL-1 and bFGF, as described by Scott-Burden et al [19]. This difference in reactivity to proinflammatory cytokines may indicate that MC, as specialized glomerular pericytes, may have a greater potential to secrete NO in response to inflammatory stimuli than their less differentiated counterparts in blood vessels of higher calibre.…”

“…Garg & Hassid have documented inhibition of mesangial proliferation by NO donor vasodilators, but cell viability was not adversely affected by NO in their study [12]. Further down this line, Scott-Burden et al reported [19] that levels of nitrite released by vascular smooth muscle cells in response to IL-1 correlated with the inhibition of thymidine incorporation. On the other hand, in a recent report Mohaupt et al [20] demonstrated lack of significant antiproliferative effect of autocrine (IL-1 -stimulated), or exogenous NO on cultured rat MC.…”

Cloning and sequencing of the proximal promoter of the rat iNOS gene: activation of NFκB is not sufficient for transcription of the iNOS gene in rat mesangial cells

“…Infiltrating activated macrophages release interleukin-ll3 (IL-I[~) and tumor necrosis factor (TNF-~), which induce the macrophage-type NO synthase (iNOS or NOS II) in mesangial cells (MCs) [3,4]. The induction of iNOS is regulated not only by these inflammatory cytokines and endotoxin but also by other factors, such as cAMP-elevating agents [5,6] and basic fibroblast growth factor [7]. In-*Corresponding author.…”

Relaxin Activates the l -Arginine–Nitric Oxide Pathway in Vascular Smooth Muscle Cells in Culture

“…30 In VSMCs, iNOS can be upregulated by damage or removal of the endothelium 31,32 as well as by endotoxins, such as bacterial LPS, and cytokines. 19,22,[33][34][35][36][37][38][39] The intracellular signal transduction mechanisms involved in the expression of iNOS are not completely known. Studies in macrophages, in which the regulation of iNOS expression…”

“…30 In VSMCs, iNOS can be upregulated by damage or removal of the endothelium 31,32 as well as by endotoxins, such as bacterial LPS, and cytokines. 19,22,[33][34][35][36][37][38][39] The intracellular signal transduction mechanisms involved in the expression of iNOS are not completely known. Studies in macrophages, in which the regulation of iNOS expression has been more extensively studied, have shown that induction of iNOS by LPS or cytokines involves the activation of transcription factor NF-B, [40][41][42] which has been shown to have a binding site on the iNOS gene promoter.…”