Nuclear factor-kappa B blockade attenuates but does not abrogate lipopolysaccharide-dependent tumor necrosis factor-alpha biosynthesis in alveolar epithelial cells

We have investigated the role that the nuclear factor (NF)-kappaB plays in regulating the biosynthesis of tumor necrosis factor (TNF)-alpha, an inflam matory cytokine. Irreversible inhibition of the proteasome complex by carbo benzoxy-L-leucyI-L-leucyl-L-leucinal (MG-132; 1-50 muM) had no inhibitory e ffect on LPS-mediated TNF-alpha biosynthesis. Furthermore, selective inhibi tion of NF-kappaB by the action of caffeic acid phenylethyl ester (CAPE; 1- 100 muM) and sulfasalazine (SSA; 0.1-10 mM), a potent and irreversible inhi bitor of NF-kappaB, partially attenuated, but did not abolish, LPS-dependen t TNF-alpha secretion. Incorporation of a selectively permeant inhibitor of NF-kappaB, SN-50 (1-20 muM), a peptide which contains the nuclear localiza tion sequence (NLS) for the p50 NF-kappaB subunit, and the amino-terminal s equence of Kaposi fibroblast growth factor to promote cell permeability, at tenuated in a dose-dependent manner LPS-mediated release of TNF-alpha. It i s concluded that the NF-kappaB pathway is partially implicated and that its blockade attenuates, but does not abrogate, LPS-dependent TNF-alpha biosyn thesis in alveolar epithelial cells. (C) 2001 Academic Press.