title: Macrophage signaling and respiratory burst.
abstract: Macrophages are key defenders of the lung and play an essential role in mediating the inflammatory response. Critical to this is the activation of the NADPH oxidase. Through receptor-mediated interactions, extracellular stimuli activate pathways that signal for the phosphorylation and assembly of the NADPH oxidase. Once the NADPH oxidase is activated, it produces superoxide and H2O2 in a process known as the respiratory burst. The involvement of O2.- and H2O2 in the antimicrobicidal function of macrophages has been assumed for many years, but it is now clear that the H2O2 produced by the respiratory burst functions as a second messenger and activates major signaling pathways in the alveolar macrophage. Both the nuclear factor-kappaB and activator protein-1 transcription factors are activated by H2O2 produced by the respiratory burst, and, since these control the inducible expression of genes whose products are part of the inflammatory response, this may be a critical link between the respiratory burst and other inflammatory responses. The c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) pathways, two members of the mitogen-activated protein kinase family, are also activated by the respiratory burst. JNK is activated by both exogenous and endogenously produced H2O2. Studies with ERK have shown that specific agonists of the respiratory burst, but not bolus H2O2, can activate this pathway. The ERK pathway also modulates the expression of genes via phosphorylation of the transcription factor Elk-1 that controls the production of the c-Fos transcription factor. Although an understanding of the mechanism of redox signaling is in its infancy, it is becoming clear that the reactive oxygen species produced by the respiratory burst have a profound effect on intracellular signaling pathways and ultimately in modulating gene expression.
authors.affiliation: Department of Environmental Health Sciences, School of Public Health, and Center for Free Radical Biology, University of Alabama at Birmingham, 35294-0022, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Iles
authors.forename: Henry Jay
authors.initials: HJ
authors.lastname: Forman
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases