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(Journal of Leukocyte Biology. 2002;71:477-486.)
© 2002 by Society for Leukocyte Biology

Hypertonicity suppresses ionophore-induced product formation and translocation of 5-lipoxygenase in human leukocytes

Eva Bürkert*, Olof Rådmark2, Bengt Samuelsson2, Dieter Steinhilber* and Oliver Werz*

* Institute of Pharmaceutical Chemistry, University of Frankfurt, Germany; and
{dagger} Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden

Correspondence: Dr. Oliver Werz, Institute of Pharmaceutical Chemistry, University of Frankfurt, Marie-Curie-Str. 9, D-60439 Frankfurt, Germany. E-mail: o.werz{at}pharmchem.uni-frankfurt.de

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 Ca2+ induced by ionophores but prevented the ionophore-induced activation of p38 MAPK-regulated MAPKAP kinases, which can phosphorylate and activate 5-LO (and cPLA2). 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.

Key Words: leukotriene • p38 MAP kinase • arachidonic acid • cytosolic phospholipase A2 • cell stress • Mono Mac 6




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 Proc. Natl. Acad. Sci. USAHome page
M. Rakonjac, L. Fischer, P. Provost, O. Werz, D. Steinhilber, B. Samuelsson, and O. Radmark
Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A4 production
PNAS, August 29, 2006; 103(35): 13150 - 13155.
[Abstract] [Full Text] [PDF]


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