5-hydroxy-6-8-11-14-eicosatetraenoic-acid and sodium-arsenite

5-Lipoxygenase (5-LO), which catalyzes the first two steps in leukotriene biosynthesis, is a target for pharmacological treatment of inflammatory disorders. Previous studies have shown that B-lymphocytes express 5-LO. Here we demonstrate that several stimuli of cell stress such as osmotic shock (sorbitol, NaCl), oxidative stress (hydrogen peroxide, diamide), chemical stress sodium arsenite, and inflammatory cytokines enhanced cellular 5-LO activity 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. These stimuli also activated p38 mitogen-activated protein (MAP) kinase and downstream MAP kinase-activated protein kinases in BL41-E95-A cells, which could phosphorylate 5-LO or heat shock protein 27 in vitro. The p38 MAP kinase inhibitor SB203580 abolished stress-induced leukotriene synthesis in B cells, 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.

Topics: Arachidonate 5-Lipoxygenase; Arachidonic Acid; Arsenites; B-Lymphocytes; Calcimycin; Calcium; Cell Line; Cell-Free System; Enzyme Activation; Enzyme Inhibitors; Hydroxyeicosatetraenoic Acids; Hypertonic Solutions; Imidazoles; Interleukin-1; Intracellular Signaling Peptides and Proteins; Ionophores; Leukotrienes; Lipoxygenase Inhibitors; Mitogen-Activated Protein Kinases; Osmotic Pressure; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinases; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Tyrosine Phosphatases; Pyridines; Sodium Compounds; Sorbitol; Subcellular Fractions; Thapsigargin; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vanadates