Glutathione, stress responses, and redox signaling in lung inflammation.
Changes in the ratio of intracellular reduced and disulfide forms of glutathione (GSH/GSSG) can affect signaling pathways that participate in various physiological responses from cell proliferation to gene expression and apoptosis. It is also now known that many proteins have a highly conserved cysteine (sulfhydryl) sequence in their active/regulatory sites, which are primary targets of oxidative modifications and thus important components of redox signaling. However, the mechanism by which oxidants and GSH/protein-cysteine-thiols actually participate in redox signaling still remains to be elucidated. Initial studies involving the role of cysteine in various proteins have revealed that cysteine-SH may mediate redox signaling via reversible or irreversible oxidative modification to Cys-sulfenate or Cys-sulfinate and Cys-sulfonate species, respectively. Oxidative stress possibly via the modification of cysteine residues activates multiple stress kinase pathways and transcription factors nuclear factor-kappaB and activator protein-1, which differentially regulate the genes for proinflammatory cytokines as well as the protective antioxidant genes. Understanding the redox signaling mechanisms for differential gene regulation may allow for the development of novel pharmacological approaches that preferentially up-regulate key antioxidants genes, which, in turn, reduce or resolve inflammation and injury. This forum article features the current knowledge on the role of GSH in redox signaling, particularly the regulation of transcription factors and downstream signaling in lung inflammation.
Rahman
Irfan
I
Department of Environmental Medicine, Division of Lung Biology and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA. irfan_rahman@urmc.rochester.edu
Biswas
Saibal K
SK
Jimenez
Luis A
LA
Torres
Martine
M
Forman
H J
HJ
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001665:Binding Sites; D049109:Cell Proliferation; D003545:Cysteine / Q000737:chemistry; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D008954:Models, Biological; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
D000975:Antioxidants; D016328:NF-kappa B; D016877:Oxidants; D018808:Transcription Factor AP-1; D005978:Glutathione; D003545:Cysteine; D010100:Oxygen