New insights into endotoxin-induced activation of macrophages: Involvementof a K+ channel in transmembrane signaling

LPS (endotoxins) activate cells of the human immune system, among which are monocytes and macrophages, to produce endogenous mediators. These regulate the immune response, but may also cause severe harm leading to septic shoc k. The activation of monocytes/macrophages by LPS is mediated by a membrane -bound LPS receptor, mCD14. As mCD14 lacks a transmembrane domain, a furthe r protein is required for the signal transducing step to the cell interior. Here we show, using excised outside-out membrane patches, that activation of a high-conductance Ca2+- and voltage-dependent potassium channel is an e arly step in the transmembrane signal transduction in macrophages. The chan nel is activated by endotoxically active LPS in a dose-dependent manner. Ch annel activation can be completely inhibited by LPS antagonists and by anti -CD14 Abs. Activation of the channel is essential for LPS-induced cytokine production as shown by its inhibition by selective K+ channel blockers.