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Blood, 5 February 2009, Vol. 113, No. 6, pp. 1326-1331.
Prepublished online as a Blood First Edition Paper on December 10, 2008; DOI 10.1182/blood-2008-07-166660.
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Submitted July 3, 2008
Accepted November 30, 2008
BK channels in innate immune functions of neutrophils and macrophages
Kirill Essin, Maik Gollasch, Susanne Rolle, Patrick Weissgerber, Matthias Sausbier, Erwin Bohn, Ingo B Autenrieth, Peter Ruth, Frederich C Luft, William M Nauseef*, and Ralph Kettritz
Department of Nephrology, HELIOS Kliniken, Berlin, Germany
Institute of Medical Microbiology and Hygiene, University Hospital, Tubingen, Germany
Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Tubingen, Tubingen, Germany
Inflammation Program, Roy and Lucille A. Carver College of Medicine, University of Iowa and Veterans Administration Medical Center, Iowa City, IA, United States
Department of Medicine, Roy and Lucille A. Carver College of Medicine, University of Iowa and Veterans Administration Medical Center, Coralville, IA, United States
* Corresponding author; email: william-nauseef{at}uiowa.edu.
Oxygen-dependent antimicrobial activity of human polymorphonuclear leukocytes (PMN) relies on the phagocyte NADPH oxidase to generate reactive oxygen species. As the oxidase transfers electrons from cytoplasmic NADPH to molecular oxygen to produce oxidants, the membrane will depolarize and concomitantly terminate oxidase activity, unless there is a mechanism to compensate the charge translocation. 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. PMN genetically lacking BK channels (BK-/-) had normal intracellular and extracellular NADPH oxidase activity in response both to receptor-independent and to phagocytic challenges. Furthermore, NADPH oxidase activity of human PMN and human macrophages was normal after treatment with BK channel inhibitors. Although BK channel inhibitors suppressed endotoxin-mediated TNF- secretion by bone marrow-derived macrophages (BMDM), BMDM of BK-/- and WT mice responded identically and exhibited the same ERK, PI3K/Akt, and NF- B activation. Based on these data, we conclude that the BK channel is not required for NADPH oxidase activity in PMN or macrophages or for endotoxin-triggered TNF- release and signal transduction BMDM.
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