title: BK channels in innate immune functions of neutrophils and macrophages.
abstract: Oxygen-dependent antimicrobial activity of human polymorphonuclear leukocytes (PMNs) relies on the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate oxidants. As the oxidase transfers electrons from NADPH the membrane will depolarize and concomitantly terminate oxidase activity, unless there is charge translocation to compensate. Most experimental data implicate proton channels as the effectors of this charge compensation, although large-conductance Ca2+-activated K+ (BK) channels have been suggested to be essential for normal PMN antimicrobial activity. To test this latter notion, we directly assessed the role of BK channels in phagocyte function, including the NADPH oxidase. PMNs genetically lacking BK channels (BK(-/-)) had normal intracellular and extracellular NADPH oxidase activity in response to both receptor-independent and phagocytic challenges. Furthermore, NADPH oxidase activity of human PMNs and macrophages was normal after treatment with BK channel inhibitors. Although BK channel inhibitors suppressed endotoxin-mediated tumor necrosis factor-alpha secretion by bone marrow-derived macrophages (BMDMs), BMDMs of BK(-/-) and wild-type mice responded identically and exhibited the same ERK, PI3K/Akt, and nuclear factor-kappaB activation. Based on these data, we conclude that the BK channel is not required for NADPH oxidase activity in PMNs or macrophages or for endotoxin-triggered tumor necrosis factor-alpha release and signal transduction BMDMs.
authors.affiliation: Department of Nephrology, Campus-Virchow, Medical Faculty of the Charité, Experimental and Clinical Research Center at the Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Kirill
authors.initials: K
authors.lastname: Essin
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: Susanne
authors.initials: S
authors.lastname: Rolle
authors.forename: Patrick
authors.initials: P
authors.lastname: Weissgerber
authors.forename: Matthias
authors.initials: M
authors.lastname: Sausbier
authors.forename: Erwin
authors.initials: E
authors.lastname: Bohn
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Autenrieth
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: William M
authors.initials: WM
authors.lastname: Nauseef
authors.forename: Ralph
authors.initials: R
authors.lastname: Kettritz
mesh_terms: D000818:Animals; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate; D007211:Indoles / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology*; D010586:Phagocytes / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016897:Respiratory Burst; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D016909:Tibial Arteries / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C048220:paxilline; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases