Liposomal delivery of purified inhibitory-kappa B alpha inhibits tumor necrosis factor-alpha-induced human vascular smooth muscle proliferation

Vessel injury results in the elaboration of various cytokines, including tu mor necrosis factor-alpha (TNF-alpha), which may influence vascular smooth muscle cell (VSMC) function and contribute to atherogenesis. We tested the hypothesis that TNF-alpha-induced VSMC proliferation requires activation of the transcription factor nuclear factor-kappa B (NF-kappa B), which could be prevented by delivery of the NF-kappa B inhibitory peptide: I kappa B al pha. TNF-alpha induced concentration-dependent human VSMC proliferation, an d neutralizing antibody to interleukin-6 reduced TNF-alpha-Induced VSMC pro liferation by 65%. In TNF-alpha-stimulated VSMCs, there was a 3-fold increa se in NF-kappa B-dependent luciferase reporter activity that was associated with degradation of I kappa B alpha. To determine an essential role for NF -kappa B in TNF-alpha-induced VSMC proliferation, recombinant I kappa B alp ha was introduced into VSMCs via liposomal delivery. Under these conditions , TNF-alpha-induced NF-kappa B nuclear translocation and DNA binding were i nhibited, NF-kappa B-dependent luciferase activity was reduced by 50%, ther e was no degradation of native I kappa B alpha detected, interleukin-6 prod uction was reduced by 54%, and VSMC proliferation was decreased by 60%. In conclusion, the mitogenic effect of TNF-alpha on human arterial VSMCs is de pendent on NF-kappa B activation and may be prevented by exogenously delive red I kappa B alpha. Furthermore, liposomal delivery of endogenous inhibito ry proteins may represent a novel, therapeutically accessible method for se lective transcriptional suppression in the response to vascular injury.