Modulation of Kv and Kir Currents by 15-Epi-Lipoxin-A4 in activated Macrophages. Implications for the Regulation of the Innate Immune Response

Abstract

Potassium channels play a pivotal role in the modulation of macrophage physiology. Blockade of voltage dependent potassium channels (Kv) channels by specific antagonists decreases macrophage cytokine production and inhibits proliferation. In the presence of aspirin, acetylated COX-2 loses activity required to form prostaglandin but maintains oxygenase activity to produce 15R-HETE from arachidonate. This intermediate product is transformed via 5-LOX into epimeric lipoxins, termed 15-epi-lipoxins (e-LXA4). Kv channels have been proposed as anti-inflammatory targets. Therefore, we studied the effects of e-LXA4 on early signaling and on Kv and inward rectifier potassium channels (Kir) in bone marrow-derived macrophages (BMDM). Experiments were performed in BMDM cells and electrophysiological recordings were performed by the whole-cell patch-clamp technique. Treatment of BMDM with e-LXA4 inhibited LPS-dependent activation of NF-κB and IKKβ activity, at the same time that protected against LPS activation-dependent apoptosis. In addition, acute treatment of LPS-stimulated BMDM cells with e-LXA4 resulted in a decrease of Kv currents, compatible with attenuation of the inflammatory response. More importantly, long-term treatment of LPS-stimulated BMDM with e-LXA4 significantly reverted LPS effects on Kv and Kir currents. These effects were mediated, at least in part, via the lipoxin receptor (ALX), since were partially reverted in the presence of a selective ALX receptor antagonist. We provide evidence for a new mechanism by which e-LXA4 contributes to inflammation resolution consisting in the reversion of LPS effects on Kv and Kir currents in macrophages.