title: Streptococcus pneumoniae stabilizes tumor necrosis factor alpha mRNA through a pathway dependent on p38 MAPK but independent of Toll-like receptors.
abstract: BACKGROUND
  Streptococcus pneumoniae is a human pathogenic bacteria and a major cause of severe invasive diseases, including pneumonia, bacteremia, and meningitis. Infections with S. pneumoniae evoke a strong inflammatory response, which plays a major role in the pathogenesis of pneumococcal disease.
  
  
  RESULTS
  In this study, we have examined how S. pneumoniae affects expression of the inflammatory cytokine tumor necrosis factor (TNF) alpha, and the molecular mechanisms involved. Secretion of TNF-alpha was strongly induced by S. pneumoniae, which was able to stabilize TNF-alpha mRNA through a mechanism dependent on the viability of the bacteria as well as the adenylate uridylate-rich elements in the 3'untranslated region of TNF-alpha mRNA. The ability of S. pneumoniae to stabilize TNF-alpha mRNA was dependent on the mitogen-activated protein kinase (MAPK) p38 whereas inhibition of Toll-like receptor signaling via MyD88 did not affect S. pneumoniae-induced mRNA stabilization. P38 was activated through a pathway involving the upstream kinase transforming growth factor-activated kinase 1 and MAPK kinase 3.
  
  
  CONCLUSIONS
  Thus, S. pneumoniae stabilizes TNF-alpha mRNA through a pathway dependent on p38 but independent of Toll-like receptors. Production of TNF-alpha may contribute significantly to the inflammatory response raised during pneumococcal infection.
authors.affiliation: Department of Infectious Diseases, Skejby Hospital - Aarhus University Hospital, DK-8200, Aarhus N, Denmark. trine.mogensen@dadlnet.dk
authors.forename: Trine H
authors.initials: TH
authors.lastname: Mogensen
authors.forename: Randi S
authors.initials: RS
authors.lastname: Berg
authors.forename: Lars
authors.initials: L
authors.lastname: Ostergaard
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
mesh_terms: D000818:Animals; D002460:Cell Line; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics* / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011008:Pneumococcal Infections / Q000276:immunology* / Q000378:metabolism*; D020871:RNA Stability / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048371:MAP Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C482531:Map2k3 protein, mouse
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