Cell type-dependent activation of 5-lipoxygenase by arachidonic acid.
5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of proinflammatory leukotrienes. We show that stimulation of polymorphonuclear leukocytes (PMNL), rat basophilic leukemia (RBL)-1, or transfected HeLa cells with arachidonic acid (AA) caused prominent 5-LO product formation that coincided with the activity of extracellular signal-regulated kinases (ERKs) and p38 mitogen-activated protein kinase. 5-LO product formation in AA-stimulated PMNL and RBL-1 cells was independent of Ca2+. However, in HeLa cells expressing a 5-LO mutant lacking potential 5-LO phosphorylation sites, removal of Ca2+ caused a prominent loss of 5-LO activity. For Mono Mac 6 (MM6) cells, AA failed to activate ERKs, and AA-induced 5-LO product formation was only minute. Also, activation of ERKs by phorbol esters did not lead to prominent 5-LO product synthesis. Instead, 5-LO activation in MM6 cells required Ca2+ or alternative signaling pathways induced by hyperosmotic stress. In summary, mechanisms for activation of 5-LO differ considerably between cell types.
Bürkert
Eva
E
Institute of Pharmaceutical Chemistry, University of Frankfurt, Marie-Curie-Strasse 9, D-60439 Frankfurt, Germany.
Szellas
Dagmar
D
Rådmark
Olof
O
Steinhilber
Dieter
D
Werz
Oliver
O
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism*; D016718:Arachidonic Acid / Q000494:pharmacology*; D001491:Basophils / Q000201:enzymology; D020013:Calcium Signaling; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases