Inhibition of the mitogen activated protein kinase, p38 alpha, prevents proinflammatory cytokine induction by human adherent mononuclear leukocytes in response to lipid loading

Atherosclerosis. 2001 Oct;158(2):331-8. doi: 10.1016/s0021-9150(01)00453-1.


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.

MeSH terms

  • Activating Transcription Factor 2
  • Cell Adhesion
  • Cholesterol / pharmacology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclooxygenase 2
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hydroxycholesterols / pharmacology
  • Imidazoles / pharmacology
  • Interleukin-1 / biosynthesis*
  • Isoenzymes
  • Leukocytes, Mononuclear / metabolism*
  • Lipids / pharmacology*
  • Lipoproteins, LDL / pharmacology
  • Membrane Proteins
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • Oxidation-Reduction
  • Phosphorylation
  • Prostaglandin-Endoperoxide Synthases
  • Pyridines / pharmacology
  • RNA, Messenger / metabolism
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • p38 Mitogen-Activated Protein Kinases


  • 4-(4-fluorophenyl)-1-(4-piperidinyl)-5-(4-pyridyl)-imidazole
  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Hydroxycholesterols
  • Imidazoles
  • Interleukin-1
  • Isoenzymes
  • Lipids
  • Lipoproteins, LDL
  • Membrane Proteins
  • Pyridines
  • RNA, Messenger
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • oxidized low density lipoprotein
  • 25-hydroxycholesterol
  • Cholesterol
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases