l-Î³-Glutamyl-l-cysteinyl-glycine (glutathione; GSH) and GSH-related enzymes in the regulation of pro- and anti-inflammatory cytokines: a signaling transcriptional scenario for redox(y) immunologic sensor(s)?

Article ID	Journal	Published Year	Pages	File Type
9141810	Molecular Immunology	2005	28 Pages	PDF

Abstract

Of the antioxidant/prooxidant mechanisms mediating the regulation of inflammatory mediators, particularly cytokines, oxidative stress-related pathways remain a cornerstone. It is conspicuous that there is a strong association between free radical accumulation (ROS/RNS; oxidative stress) and the evolution of inflammation and inflammatory-related responses. The scenario that upholds a consensus on the aforementioned is still evolving to unravel, from an immunologic perspective, the molecular mechanisms associated with ROS/RNS-dependent inflammation. Cytokines are keynote players when it comes to defining an intimate relationship among reduction-oxidation (redox) signals, oxidative stress and inflammation. How close we are to identifying the molecular basis of this intricate association should be weighed against the involvement of specific signaling molecules and, potentially, transcription factors. l-Î³-Glutamyl-l-cysteinyl-glycine, or glutathione (GSH), an antioxidant thiol, has shaped, and still is refining, the face of oxidative signaling in terms of regulating the milieu of inflammatory mediators, ostensibly via the modulation (expression/repression) of oxygen- and redox-responsive transcription factors, hence termed redox(y)-sensitive cofactors. When it comes to the arena of oxygen sensing, oxidative stress and inflammation, nuclear factor-ÎºB (NF-ÎºB) and hypoxia-inducible factor-1Î± (HIF-1Î±) are key players that determine antioxidant/prooxidant responses with oxidative challenge. It is the theme therein to underlie current understanding of the molecular association hanging between oxidative stress and the evolution of inflammation, walked through an elaborate discussion on the role of transcription factors and cofactors. Would that classify glutathione and other redox signaling cofactors as potential anti-inflammatory molecules emphatically remains of particular interest, especially in the light of identifying upstream and downstream molecular pathways for conceiving therapeutic, alleviating strategy for oxidant-mediated, inflammatory-related disease conditions.

Keywords

NF-κB EGF LPS COX DEX Jnk mAb MCP Concanavalin A CAPE MBP BHA GSH GST HEK NAC GPX TCr EPO NAL ERK GSSG iNOS RNS Hsp SRF pKa IκB N-acetyl-l-cysteine NGF NMDA N-methyl-d-aspartate AP-1 HIF-1α PKC HBMEC TGF BCNU PAK BSO γ-GT GSNO S-nitrosoglutathione ARNT PDGF HRE VHL Trx ARDS phorbol 12-myristate 13-acetate IDDM ICAM VCAM RCC VEGFR TNFR SIV GalN GEF ConA RTK Jun N-terminal kinase GSTP MKP PDTC SAPK UPJ γ-GCS MAPK phosphatases MAPKK Dem MAPKKK MLK Redox factor JIP PTK PAEC S-nitroso-N-acetylpenicillamine TNF oxidized glutathione disulfide 1,3-Bis (2-chloroethyl)-1-nitrosourea l-γ-glutamyl-l-cysteinyl-glycine natural killer bHLH-PAS Dimethylthiourea DMTU I/R l-buthionine-(S,R)-sulfoximine PMA MAPK MAPK kinase MAPK kinase kinase O2−ROS γ-glutamyl transpeptidase γ-glutamylcysteine synthetase Hydrogen peroxide STAT Antioxidant Monoclonal antibody cyclooxygenase Superoxide radical anion Ureteropelvic junction erythropoietin von Hippel-Lindau caffeic acid phenethyl ester inflammation AIDS interferon IFN interleukin transforming growth factor thioredoxin Dexamethasone diethyl maleate Insulin-dependent diabetes mellitus Hydroxyl radical Redox LAT SOD porcine aortic endothelial cell Endothelial cell Human brain microvascular endothelial cells inducible nitric oxide synthase Acute respiratory distress syndrome acquired immune deficiency syndrome Superoxide dismutase Cytokine GAP SNAP Pro-oxidant epidermal growth factor antioxidant response element hypoxia response element Vascular endothelial growth factor Vascular Endothelial Growth Factor (VEGF)platelet-derived growth factor nerve growth factor tumor necrosis factor nuclear factor-κB serum response factor Linker for activation of T cells lipopolysaccharide Signal transducer and activator of transcription METH Methamphetamine REF RANTES intercellular adhesion molecule vascular cell adhesion molecule Nitric oxide ARE H2O2 butylated hydroxyanisole HIV human immunodeficiency virus Protein tyrosine kinase Heat shock protein monocyte chemoattractant protein Protein phosphatase GTPase activating proteins Myelin basic protein protein kinase A Protein kinase C mitogen-activated protein kinase Renal cell carcinoma Reduction–oxidation human embryonic kidney extracellular signal-regulated kinase p21-activated kinase stress-activated protein kinases Galactosamine Glutathione Glutathione S-transferase Pi glutathione peroxidase reactive nitrogen species Reactive oxygen species TNF receptor VEGF receptor receptor tyrosine kinases T-cell receptor glucocorticoid receptor