p38 MAP kinase mediates stress-induced leukotriene synthesis in a human B-lymphocyte cell line

5-Lipoxygenase (5-LO), which catalyzes the first two steps in leukotriene b iosynthesis, is a target for pharmacological treatment of inflammatory diso rders. Previous studies have shown that B-lymphocytes express 5-LO. Here we demonstrate that several stimuli of cell stress such as osmotic shock (sor bitol, NaCI), oxidative stress (hydrogen peroxide, diamide), chemical stres s sodium arsenite, and inflammatory cytokines enhanced cellular 5-LO activi ty in a B cell line (BL41-E95-A), when added simultaneously with ionophore plus arachidonate. It is interesting that sorbitol alone was sufficient for 5-LO product formation in the presence of exogenous arachidonic acid. Thes e stimuli also activated p38 mitogen-activated protein (MAP) kinase and dow nstream MAP kinase-activated protein kinases in BL41-E95-A cells, which cou ld phosphorylate 5-LO or heat shock protein 27 in vitro. The p38 MAP kinase inhibitor SB203580 abolished stress-induced leukotriene synthesis in B cel ls, without inhibition of 5-LO catalytic activity in cell-free systems. Our results indicate that p38 MAP kinase activation by cell stress is required for efficient leukotriene synthesis in B-lymphocytes.