title: Hypertonicity suppresses ionophore-induced product formation and translocation of 5-lipoxygenase in human leukocytes.
abstract: 5-Lipoxygenase (5-LO) initiates the biosynthesis of proinflammatory leukotrienes from arachidonic acid (AA). Here, we demonstrate that hypertonicity suppresses ionophore-induced 5-LO product formation reversibly in isolated human polymorphonuclear leukocytes (PMNL) and in Mono Mac 6 cells. Hypertonicity blocked the liberation of AA and abrogated translocation of 5-LO to the nuclear membrane. Accordingly, in the presence of exogenous AA, 5-LO product formation was less affected. The effects of hypertonicity were a result of cell shrinkage and not cytosolic hyperosmolarity. Hypertonicity did not inhibit the rapid increase in intracellular Ca(2)(+) induced by ionophores but prevented the ionophore-induced activation of p38 MAPK-regulated MAPKAP kinases, which can phosphorylate and activate 5-LO (and cPLA(2)). In summary, we show that hypertonicity blocks agonist-induced release of AA, 5-LO product formation, and translocation and in parallel, prevents activation of p38 MAPK and downstream 5-LO kinases in leukocytes.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Frankfurt, Marie-Curie-Strasse 9, D-60439 Frankfurt, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Bürkert
authors.forename: Olof
authors.initials: O
authors.lastname: Rådmark
authors.forename: Bengt
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000096:biosynthesis*; D002460:Cell Line; D005950:Glucose Solution, Hypertonic; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects
chemical_list: D005950:Glucose Solution, Hypertonic; D007476:Ionophores; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase