title: Involvement of a membrane potassium channel in heparan sulphate-induced activation of macrophages.
abstract: Increasing evidence has demonstrated that Toll-like receptor 4 (TLR4) -mediated systemic inflammatory response syndrome accompanied by multiple organ failure, is one of the most common causes of death in patients with severe acute pancreatitis. Recent reports have revealed that heparan sulphate (HS) proteoglycan, a component of extracellular matrices, potentiates the activation of intracellular pro-inflammatory responses via TLR4, contributing to the aggravation of acute pancreatitis. However, little is known about the participants in the HS/TLR4-mediated inflammatory cascades. Our previous work provided a clue that a membrane potassium channel (MaxiK) is responsible for HS-induced production of inflammatory cytokines. Therefore, in this report we attempted to reveal the roles of MaxiK in the activation of macrophages stimulated by HS. Our results showed that incubation of RAW264.7 cells with HS up-regulated MaxiK and TLR4 expression levels. HS could also activate MaxiK channels to promote the efflux of potassium ions from cells, as measured by the elevated activity of caspase-1, whereas this was significantly abolished by treatment with paxilline, a specific blocker of the MaxiK channel. Moreover, it was found that paxilline substantially inhibited HS-induced activation of several different transcription factors in macrophages, including nuclear factor-κB, p38 and interferon regulatory factor-3, followed by decreased production of tumour necrosis factor-α and interferon-β. Taken together, our investigation provides evidence that the HS/TLR4-mediated intracellular inflammatory cascade depends on the activation of MaxiK, which may offer an important opportunity for a new approach in therapeutic strategies of severe acute pancreatitis.
authors.affiliation: Department of Pharmacy, General Hospital of Chengdu Military Region, Chengdu, China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Ren
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Fu-Zhou
authors.initials: FZ
authors.lastname: Tian
authors.forename: Kai-Hua
authors.initials: KH
authors.lastname: Fan
authors.forename: Bo-Tao
authors.initials: BT
authors.lastname: Yu
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Jin
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Tan
authors.forename: Long
authors.initials: L
authors.lastname: Cheng
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006497:Heparan Sulfate / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020170:Caspase 1; D006497:Heparan Sulfate; D050838:Interferon Regulatory Factor-3; D053583:Interleukin-1beta; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011188:Potassium; D026902:Potassium Channel Blockers; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C494233:Irf3 protein, mouse; C493487:Tlr4 protein, mouse
keywords: MaxiK; Toll-like receptor 4; heparan sulphate; paxilline