title: 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.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Moreno
authors.forename: Patricia
authors.initials: P
authors.lastname: Prieto
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Macías
authors.forename: María
authors.initials: M
authors.lastname: Pimentel-Santillana
authors.forename: Alicia
authors.initials: A
authors.lastname: de la Cruz
authors.forename: Paqui G
authors.initials: PG
authors.lastname: Través
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.forename: Carmen
authors.initials: C
authors.lastname: Valenzuela
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000502:physiology; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D017136:Ion Transport; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051666:Kv1.5 Potassium Channel / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D044045:Lipoxins / Q000494:pharmacology*; D008262:Macrophage Activation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000502:physiology; D012604:Scorpion Venoms / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D015854:Up-Regulation
chemical_list: D018793:Interleukin-13; C489461:Kir2.1 channel; D051664:Kv1.3 Potassium Channel; D051666:Kv1.5 Potassium Channel; D008070:Lipopolysaccharides; D044045:Lipoxins; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D012604:Scorpion Venoms; C481578:formyl peptide receptor 2, mouse; C040527:lipoxin A4; D015847:Interleukin-4; C077910:margatoxin; D011188:Potassium; D002118:Calcium