title: Inhibition of the mitogen activated protein kinase, p38 alpha, prevents proinflammatory cytokine induction by human adherent mononuclear leukocytes in response to lipid loading.
abstract: Macrophage infiltration, inflammatory processes and oxidatively modified low density lipoprotein (LDL) are known contributing factors in the formation of the atherosclerotic plaque. To determine whether a direct link might exist between these factors, we examined the effect of oxidized LDL upon proinflammatory cytokine production in adherent human peripheral blood mononuclear leukocytes. Oxidized LDL, as well as a combination of cholesterol and 25-hydroxycholesterol, induced tumor necrosis factor-alpha (TNFalpha) and interleukin-1 beta (IL-1 beta) mRNA as measured by quantitative real time PCR, by a maximum of two- to fourfold following a 24-h incubation. Analysis of cell culture supernatants revealed a concomitant stimulation of TNFalpha and IL-1 beta secreted protein as determined by ELISA. Treatment of human peripheral blood mononuclear leukocytes with oxidized LDL or the combination of cholesterol and 25-hydroxycholesterol caused activation of p38 alpha as determined by the ability of immunoprecipitated p38 to phosphorylate an ATF-2 fusion protein, a surrogate substrate of p38 alpha. VK-19911 (Pyridine, 4-[4-(4-fluorophenyl)-1-(4-piperidinyl)-1H-imidazol-5-yl]-dihydrochloride), a specific inhibitor of p38 alpha, prevented the induction of TNFalpha and IL-1 beta by oxidized LDL in a dose-dependent manner. Activated p38 alpha is known to be involved in the stabilization of cyclooxygenase-2 mRNA in response to stimuli such as lipopolysaccharide; however, in the setting of oxidized LDL-induced p38 alpha activation, COX-2 mRNA levels were not affected. Taken together, the data imply a potential role for p38 alpha activation in lipid-associated inflammatory processes.
authors.affiliation: Scios Inc., 820 West Maude Ave., Sunnyvale, CA 94086, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.forename: G F
authors.initials: GF
authors.lastname: Schreiner
authors.forename: S
authors.initials: S
authors.lastname: Chakravarty
authors.forename: D Y
authors.initials: DY
authors.lastname: Liu
authors.forename: A H
authors.initials: AH
authors.lastname: Joly
mesh_terms: D051698:Activating Transcription Factor 2; D002448:Cell Adhesion; D002784:Cholesterol / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis*; D007527:Isoenzymes; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008055:Lipids / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C107383:4-(4-fluorophenyl)-1-(4-piperidinyl)-5-(4-pyridyl)-imidazole; C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D007093:Imidazoles; D007375:Interleukin-1; D007527:Isoenzymes; D008055:Lipids; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D011725:Pyridines; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; C007997:25-hydroxycholesterol; D002784:Cholesterol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases