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MaxiK Blockade Selectively Inhibits the Lipopolysaccharide-Induced IB-/NF-B Signaling Pathway in Macrophages¹

Martin Papavlassopoulos^*,, Cordula Stamme^*,, Lutz Thon^||, Dieter Adam^||, Doris Hillemann^*,, Ulrich Seydel^*,¶ and Andra B. Schromm^2,*,

^* Research Center Borstel, Center for Medicine and Biosciences, Department of Immunochemistry and Biochemical Microbiology, Emmy-Noether Group Immunobiophysics, Division of Cellular Pneumology, Division of Mycobacteriology, and ^¶ Division of Biophysics, Borstel, Germany; and ^|| Institute of Immunology, University Clinic of Schleswig-Holstein Campus Kiel, Kiel, Germany

Macrophages have a pivotal function in innate immunity against bacterial infections. They are present in all body compartments and able to detect invading microorganisms with high sensitivity. LPS (endotoxin) of Gram-negative bacteria is among the most potent stimuli for macrophages and initiates a wide panel of cellular activation responses. The release of mediators such as TNF- and ILs is essential for the initiation of a proinflammatory antibacterial response. Here, we show that blockade of the large-conductance Ca²⁺-activated potassium channel MaxiK (BK) inhibited cytokine production from LPS-stimulated macrophages at the transcriptional level. This inhibitory effect of channel blockade was specific to stimulation with LPS and affected neither stimulation of macrophages with the cytokine TNF- nor LPS-induced activation of cells that do not express MaxiK. Investigation of the upstream intracellular signaling pathways induced by LPS revealed that the blockade of MaxiK selectively inhibited signaling pathways leading to the activation of the transcription factor NF-B and the MAPK p38, whereas activation of ERK was unaffected. We present data supporting that proximal regulation of the inhibitory factor IB- is critically involved in the observed inhibition of NF-B translocation. Using alveolar macrophages from rats, we could show that the necessity of MaxiK function in activation of NF-B and subsequent cytokine production is not restricted to in vitro-generated monocyte-derived macrophages but also can be observed in primary cells. Thus, MaxiK appears to be a central molecule in the NF-B-dependent inflammatory response of macrophages to bacterial LPS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Deutsche Forschungsgemeinschaft (SCHR 621/2-1, SFB 367 Project B8, and DFG STA 609/1-3).

² Address correspondence and reprint requests to Dr. Andra Schromm, Research Center Borstel, Department of Immunochemistry and Biochemical Microbiology, Emmy-Noether Group Immunobiophysics, Parkallee 10, 23845 Borstel, Germany. E-mail address: aschromm{at}fz-borstel.de

³ Abbreviations used in this paper: LBP, LPS-binding protein; TIR, Toll/IL-1R.