Blockade of Smooth Muscle Cell Migration and Proliferation in Baboon Aortic Explants by Interleukin-1β and Tumor Necrosis Factor-α Is Nitric Oxide-Dependent and Nitric Oxide-Independent

Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) are found in injured and atherosclerotic vessels and have been shown to influence smooth muscle cell (SMC) function in vitro. We have investigated the effects of IL-1beta and TNFalpha on SMC migration and proliferation in baboon aortic explants, an in vitro model of arterial injury. Because platelet-derived growth factor (PDGF) is also present in the vessel wall, we have studied the interaction of PDGF with the cytokines. IL-1beta and TNFalpha inhibited migration of SMCs and synthesis of DNA by SMCs. Cell death (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells and total DNA) was not altered by the cytokines. The cytokines increased levels of nitrite in the medium and L-nitroarginine partly reversed the inhibitory effects of the cytokines indicating a role for nitric oxide in these inhibitory effects. Treatment with indomethacin partially reversed the inhibition of migration, but not DNA synthesis by IL-1beta suggesting cyclooxygenase products play an inhibitory role in migration. PDGF-BB reversed the inhibitory effect of the cytokines on SMC migration, but not mitogenesis, without changing levels of nitrite in the medium. These data show that IL-1beta and TNFalpha decrease primate SMC migration and proliferation in arterial tissue partly through production of NO, and that PDGF antagonizes the effect of the cytokines. IL-1beta and TNFalpha may act directly to limit injury-induced intimal hyperplasia by decreasing SMC migration and proliferation.