Modulation of Voltage-Dependent and Inward Rectifier Potassium Channels by 15-Epi-Lipoxin-A4 in Activated Murine Macrophages: Implications in Innate Immunity

Abstract

Potassium channels modulate macrophage physiology. Blockade of voltage-dependent potassium channels (Kv) by specific antagonists decreases macrophage cytokine production and inhibits proliferation. In the presence of aspirin, acetylated cyclooxygenase-2 loses the activity required to synthesize PGs but maintains the oxygenase activity to produce 15R-HETE from arachidonate. This intermediate product is transformed via 5-LOX into epimeric lipoxins, termed 15-epi-lipoxins (15-epi-lipoxin A4 [e-LXA4]). Kv have been proposed as anti-inflammatory targets. Therefore, we studied the effects of e-LXA4 on signaling and on Kv and inward rectifier potassium channels (Kir) in mice bone marrow–derived macrophages (BMDM). Electrophysiological recordings were performed in these cells by the whole-cell patch-clamp technique. Treatment of BMDM with e-LXA4 inhibited LPS-dependent activation of NF-κB and IκB kinase β activity, protected against LPS activation–dependent apoptosis, and enhanced the accumulation of the Nrf-2 transcription factor. Moreover, treatment of LPS-stimulated BMDM with e-LXA4 resulted in a rapid decrease of Kv currents, compatible with attenuation of the inflammatory response. Long-term treatment of LPS-stimulated BMDM with e-LXA4 significantly reverted LPS effects on Kv and Kir currents. Under these conditions, e-LXA4 decreased the calcium influx versus that observed in LPS-stimulated BMDM. These effects were partially mediated via the lipoxin receptor (ALX), because they were significantly reverted by a selective ALX receptor antagonist. We provide evidence for a new mechanism by which e-LXA4 contributes to inflammation resolution, consisting of the reversion of LPS effects on Kv and Kir currents in macrophages.

Inward rectifier potassium currents in mammalian skeletal muscle fibres

“…In fact, several putative glycosylation and phosphorylation sites (for protein kinases A and C and tyrosine kinase) have been identified in Kir2.1 (Yang et al 2003). Our observation of a double band for Kir2.1 is in agreement with reports of small and large molecular weight bands in CHO and COS cells transfected with IKir2.1 (NeuroMab and Fang et al (2005), respectively), and with the same observation in a preparation from murine macrophages tested with an antibody comparable to ours (Moreno et al 2013).…”

“…(), respectively), and with the same observation in a preparation from murine macrophages tested with an antibody comparable to ours (Moreno et al . ).…”

Effect of lysophosphatidic acid on the immune inflammatory response and the connexin 43 protein in myocardial infarction

“…It was deduced that LPA had a dose-dependent effect on the K v current. The electrophysiological characteristics (current amplitude and activation, and inactivation voltage range) of K v in the present study were concordant with those of previous reports (14,15). (Fig.…”

Mechanisms of the Immunological Effects of Volatile Anesthetics: A Review

“…Activation of the GABA A Rreduced IL-6 and IL-12 production in LPS stimulated macrophages(92), whereas stimulation of nAChR α4β2 with agonists attenuated intracellular calcium and NF-kB activation(32), but enhanced phagocytosis(31). Both Kca3.1 and Kv1.3 regulate calcium influx(93), and their blockade reduced chemotactic migration (94, 95). Nav1.5 is expressed on the late endosome and contributes to the generation of prolonged and localized calcium oscillations during phagocytosome formation(67).…”