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 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.
Werz
O
O
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institute, Stockholm, Sweden.
Klemm
J
J
Rådmark
O
O
Samuelsson
B
B
D001094:Arachidonate 5-Lipoxygenase / Q000032:analysis / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D018053:Arsenites / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D002474:Cell-Free System; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D006982:Hypertonic Solutions / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009997:Osmotic Pressure; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D017670:Sodium Compounds / Q000494:pharmacology; D013012:Sorbitol / Q000008:administration & dosage; D013347:Subcellular Fractions / Q000201:enzymology; D019284:Thapsigargin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D001094:Arachidonate 5-Lipoxygenase; D016718:Arachidonic Acid; D018053:Arsenites; D000001:Calcimycin; D002118:Calcium; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D006982:Hypertonic Solutions; D007093:Imidazoles; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011725:Pyridines; D017670:Sodium Compounds; D013012:Sorbitol; D019284:Thapsigargin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014638:Vanadates; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C017947:sodium arsenite; C093642:SB 203580