title: Cytokine mRNA decay is accelerated by an inhibitor of p38-mitogen-activated protein kinase.
abstract: OBJECTIVE
  To identify the site(s) in tumor necrosis factor (TNFalpha), interleukin-6 (IL-6), and macrophage inflammatory protein-1alpha (MIP-1alpha) biosynthesis that is blocked by SB202190, a selective inhibitor of p38-mitogen activated protein kinase (p38).
  
  
  METHODS
  Human blood monocytes isolated by centrifugal elutriation.
  
  
  METHODS
  Monocytes were stimulated with lipopolysaccharide in the presence of 0, 0.3, 1 and 3 microM SB202190. Induced TNFalpha, IL-6, and MIP-1alpha protein and mRNA were measured by ELISA and quantitative RT-PCR, respectively. The half-lives of cytokine mRNA levels were determined following treatment of cells with actinomycin D or SB202190.
  
  
  RESULTS
  SB202190 suppressed >60% of lipopolysaccharide-induced TNFalpha, IL-6, and MIP-1alpha protein and mRNA expression. Suppressed mRNA levels could be attributed to a >2 to 7-fold reduction in cytokine mRNA half-lives. In contrast, SB202190 did not destabilize mRNAs encoding interferon-induced gene 15 protein and glyceraldehyde-3-phosphate dehydrogenase.
  
  
  CONCLUSIONS
  Specific mRNA destabilization represents an important and novel site of action for the cytokine suppressive effects of p38 inhibitors.
authors.affiliation: Department of Biology, Amgen Inc., Boulder, CO 80301, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Pawlowski
authors.forename: S T
authors.initials: ST
authors.lastname: Wathen
authors.forename: S D
authors.initials: SD
authors.lastname: Kinney
authors.forename: H S
authors.initials: HS
authors.lastname: Lichenstein
authors.forename: C L
authors.initials: CL
authors.lastname: Manthey
mesh_terms: D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000097:blood; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000097:blood / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000097:blood / Q000737:chemistry / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D020928:Mitogen-Activated Protein Kinases; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole