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Redox signaling-mediated regulation of lipopolysaccharide-induced proinflammatory cytokine biosynthesis in alveolar epithelial cells.
Antioxid Redox Signal. 2002 Feb; 4(1):179-93.AR

Abstract

The regulation of cytokine gene transcription and biosynthesis involves the reduction-oxidation (redox)-sensitive nuclear factor-kappaB (NF-kappaB), whose activation is mediated by an upstream kinase that regulates the phosphorylation of inhibitory-kappaB (IkappaB). It was hypothesized that lipopolysaccharide (LPS)-induced biosynthesis of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in vitro is regulated by redox equilibrium. In alveolar epithelial cells, we investigated the role of L-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), which inhibits glutathione oxidized disulfide reductase, pyrrolidine dithiocarbamate (PDTC), an antioxidant/prooxidant thiuram, and N-acetyl-L-cysteine (NAC), an antioxidant and GSH precursor, in regulating LPS-induced cytokine biosynthesis and IkappaB-alpha/NF-kappaB signaling. BSO blockaded the phosphorylation of IkappaB-alpha, reduced its degradation, and inhibited NF-kappaB activation, besides augmenting LPS-mediated biosynthesis of cytokines. BCNU up-regulated LPS-induced release of cytokines, an effect associated with partial phosphorylation/degradation of IkappaB-alpha and inhibition of the DNA binding activity. PDTC, which partially affected LPS-induced IkappaB-alpha phosphorylation/degradation, otherwise blockading NF-kappaB activation, reduced LPS-dependent up-regulation of cytokine release. Pretreatment with BSO did not abolish the NAC-dependent reduction of LPS-induced cytokine release, despite the fact that NAC marginally amplified IkappaB-alpha phosphorylation/degradation and suppressed NF-kappaB activation. These results indicate that cytokines are redox-sensitive mediators and that the IkappaB-alpha/NF-kappaB pathway is redox-sensitive and differentially implicated in mediating redox-dependent regulation of LPS-induced release of proinflammatory cytokines.

Authors+Show Affiliations

Oxygen Signaling Group, Center for Research into Human Development, Tayside Institute of Child Health, Faculty of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK. haddadj@anesthesia.ucsf.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11970852

Citation

Haddad, John J., and Stephen C. Land. "Redox Signaling-mediated Regulation of Lipopolysaccharide-induced Proinflammatory Cytokine Biosynthesis in Alveolar Epithelial Cells." Antioxidants & Redox Signaling, vol. 4, no. 1, 2002, pp. 179-93.
Haddad JJ, Land SC. Redox signaling-mediated regulation of lipopolysaccharide-induced proinflammatory cytokine biosynthesis in alveolar epithelial cells. Antioxid Redox Signal. 2002;4(1):179-93.
Haddad, J. J., & Land, S. C. (2002). Redox signaling-mediated regulation of lipopolysaccharide-induced proinflammatory cytokine biosynthesis in alveolar epithelial cells. Antioxidants & Redox Signaling, 4(1), 179-93.
Haddad JJ, Land SC. Redox Signaling-mediated Regulation of Lipopolysaccharide-induced Proinflammatory Cytokine Biosynthesis in Alveolar Epithelial Cells. Antioxid Redox Signal. 2002;4(1):179-93. PubMed PMID: 11970852.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Redox signaling-mediated regulation of lipopolysaccharide-induced proinflammatory cytokine biosynthesis in alveolar epithelial cells. AU - Haddad,John J, AU - Land,Stephen C, PY - 2002/4/24/pubmed PY - 2002/8/13/medline PY - 2002/4/24/entrez SP - 179 EP - 93 JF - Antioxidants & redox signaling JO - Antioxid Redox Signal VL - 4 IS - 1 N2 - The regulation of cytokine gene transcription and biosynthesis involves the reduction-oxidation (redox)-sensitive nuclear factor-kappaB (NF-kappaB), whose activation is mediated by an upstream kinase that regulates the phosphorylation of inhibitory-kappaB (IkappaB). It was hypothesized that lipopolysaccharide (LPS)-induced biosynthesis of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in vitro is regulated by redox equilibrium. In alveolar epithelial cells, we investigated the role of L-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), which inhibits glutathione oxidized disulfide reductase, pyrrolidine dithiocarbamate (PDTC), an antioxidant/prooxidant thiuram, and N-acetyl-L-cysteine (NAC), an antioxidant and GSH precursor, in regulating LPS-induced cytokine biosynthesis and IkappaB-alpha/NF-kappaB signaling. BSO blockaded the phosphorylation of IkappaB-alpha, reduced its degradation, and inhibited NF-kappaB activation, besides augmenting LPS-mediated biosynthesis of cytokines. BCNU up-regulated LPS-induced release of cytokines, an effect associated with partial phosphorylation/degradation of IkappaB-alpha and inhibition of the DNA binding activity. PDTC, which partially affected LPS-induced IkappaB-alpha phosphorylation/degradation, otherwise blockading NF-kappaB activation, reduced LPS-dependent up-regulation of cytokine release. Pretreatment with BSO did not abolish the NAC-dependent reduction of LPS-induced cytokine release, despite the fact that NAC marginally amplified IkappaB-alpha phosphorylation/degradation and suppressed NF-kappaB activation. These results indicate that cytokines are redox-sensitive mediators and that the IkappaB-alpha/NF-kappaB pathway is redox-sensitive and differentially implicated in mediating redox-dependent regulation of LPS-induced release of proinflammatory cytokines. SN - 1523-0864 UR - https://www.unboundmedicine.com/medline/citation/11970852/Redox_signaling_mediated_regulation_of_lipopolysaccharide_induced_proinflammatory_cytokine_biosynthesis_in_alveolar_epithelial_cells_ L2 - https://www.liebertpub.com/doi/10.1089/152308602753625942?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -