Nuclear factor-kappab 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 inflammatory cytokine. Irreversible inhibition of the proteasome complex by carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG-132; 1-50 microM) had no inhibitory effect on LPS-mediated TNF-alpha biosynthesis. Furthermore, selective inhibition of NF-kappaB by the action of caffeic acid phenylethyl ester (CAPE; 1-100 microM) and sulfasalazine (SSA; 0.1-10 mM), a potent and irreversible inhibitor of NF-kappaB, partially attenuated, but did not abolish, LPS-dependent TNF-alpha secretion. Incorporation of a selectively permeant inhibitor of NF-kappaB, SN-50 (1-20 microM), a peptide which contains the nuclear localization sequence (NLS) for the p50 NF-kappaB subunit, and the amino-terminal sequence of Kaposi fibroblast growth factor to promote cell permeability, attenuated in a dose-dependent manner LPS-mediated release of TNF-alpha. It is concluded that the NF-kappaB pathway is partially implicated and that its blockade attenuates, but does not abrogate, LPS-dependent TNF-alpha biosynthesis in alveolar epithelial cells.
Haddad
J J
JJ
Oxygen Signalling Group, Center for Research into Human Development, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK. j.j.haddad@dundee.ac.uk
Land
S C
SC
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D021122:Protein Subunits; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D016328:NF-kappa B; D010455:Peptides; D021122:Protein Subunits; D011994:Recombinant Proteins; C118258:SN50 peptide; D014409:Tumor Necrosis Factor-alpha