Blockade of smooth muscle cell migration and proliferation in baboon aortic explants by interleukin-1beta and tumor necrosis factor-alpha 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.
Kenagy
R D
RD
Department of Surgery, University of Washington, Seattle, WA 98195-6410, USA. rkenagy@u.washington.edu
Clowes
A W
AW
D000818:Animals; D001011:Aorta; D017209:Apoptosis; D000077214:Becaplermin; D002455:Cell Division; D002465:Cell Movement; D004247:DNA / Q000096:biosynthesis; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D009573:Nitrites; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D014409:Tumor Necrosis Factor-alpha; D000077214:Becaplermin; D019335:Nitroarginine; D009569:Nitric Oxide; D004247:DNA; D007213:Indomethacin