Hypertonicity suppresses ionophore-induced product formation and translocation of 5-lipoxygenase in human leukocytes.
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.
Bürkert
Eva
E
Institute of Pharmaceutical Chemistry, University of Frankfurt, Marie-Curie-Strasse 9, D-60439 Frankfurt, Germany.
Rådmark
Olof
O
Samuelsson
Bengt
B
Steinhilber
Dieter
D
Werz
Oliver
O
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
D005950:Glucose Solution, Hypertonic; D007476:Ionophores; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase