Redox Signaling-Mediated Regulation of Lipopolysaccharide-Induced Proinflammatory Cytokine Biosynthesis in Alveolar Epithelial Cells

John J. Haddad, Stephen C. Land

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The regulation of cytokine gene transcription and biosynthesis involves the reduction-oxidation (redox)-sensitive nuclear factor-κB (NF-κB) whose activation is mediated by an upstream kinase that regulates the phosphorylation of inhibitory-κB (IκB). It was hypothesized that lipopolysaccharide (LPS)-induced biosynthesis of interleukin-1β interleukin-6 and tumor necrosis factor-α 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 γ-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 IκB-α/NF-κB signaling. BSO blockaded the phosphorylation of IκB-α reduced its degradation and inhibited NF-κB activation besides augmenting LPS-mediated biosynthesis of cytokines. BCNU up-regulated LPS-induced release of cytokines an effect associated with partial phosphorylation/degradation of IκB-α and inhibition of the DNA binding activity. PDTC which partially affected LPS-induced IκB-α phosphorylation/degradation otherwise blockading NF-κB 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 IκB-α phosphorylation/degradation and suppressed NF-κB activation. These results indicate that cytokines are redox-sensitive mediators and that the IκB-α/NF-κB pathway is redox-sensitive and differentially implicated in mediating redox-dependent regulation of LPS-induced release of proinflammatory cytokines.

Original languageEnglish
Pages (from-to)179-193
Number of pages15
JournalAntioxidants and Redox Signaling
Volume4
Issue number1
DOIs
Publication statusPublished - Feb 2002

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