Streptococcus pneumoniae stabilizes tumor necrosis factor alpha mRNA through a pathway dependent on p38 MAPK but independent of Toll-like receptors.
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.
Mogensen
Trine H
TH
Department of Infectious Diseases, Skejby Hospital - Aarhus University Hospital, DK-8200, Aarhus N, Denmark. trine.mogensen@dadlnet.dk
Berg
Randi S
RS
Ostergaard
Lars
L
Paludan
Søren R
SR
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
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
J Infect Dis. 2005 May 1;191(9):1538-47
15809914
J Mol Med (Berl). 2004 Jul;82(7):434-48
15175863
Genes Dev. 2005 Nov 15;19(22):2668-81
16260493
Infect Immun. 2002 Nov;70(11):6504-8
12379738
Biochem J. 2007 Jun 1;404(2):179-90
17348859
Nature. 1993 Aug 26;364(6440):798-802
8395024
Brain. 2004 Jun;127(Pt 6):1437-45
15115715
Int J Antimicrob Agents. 2005 Sep;26(3):188-96
16099623
J Biol Chem. 2004 Aug 27;279(35):36426-32
15215247
Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3513-22
15452057
Cell. 2006 Feb 24;124(4):783-801
16497588
J Infect Dis. 2003 Oct 1;188(7):1040-8
14513425
N Engl J Med. 2001 Oct 11;345(15):1098-104
11596589
Annu Rev Biochem. 2005;74:355-83
15952891
Immunity. 1999 Mar;10(3):387-98
10204494
Cell Signal. 2004 Oct;16(10):1113-21
15240006
Int J Antimicrob Agents. 2002 Feb;19(2):85-93
11850160
Nature. 2000 Dec 7;408(6813):740-5
11130078
Cytokine Growth Factor Rev. 2007 Jun-Aug;18(3-4):335-43
17493863
Nat Immunol. 2005 Nov;6(11):1087-95
16186825
Mol Cell Biol. 2006 Mar;26(6):2399-407
16508014
Cell Mol Life Sci. 2001 Feb;58(2):266-77
11289308
Biochem Soc Trans. 2002 Nov;30(Pt 6):952-8
12440953
J Leukoc Biol. 2006 Aug;80(2):267-77
16731773
J Immunol. 2006 Jul 1;177(1):657-64
16785564
J Inflamm. 1995-1996;46(1):1-12
8832967
J Med Microbiol. 2002 Feb;51(2):98-104
11863272
Nature. 2001 Jul 19;412(6844):346-51
11460167
Lancet Infect Dis. 2002 Dec;2(12):721-36
12467688
EMBO J. 2000 Aug 1;19(15):4154-63
10921895
Cell Microbiol. 2007 Mar;9(3):633-44
17004992
Nat Rev Immunol. 2004 Jul;4(7):499-511
15229469
Infect Immun. 2004 Feb;72(2):788-94
14742522
J Immunol. 1999 Jul 1;163(1):1-5
10384090
J Leukoc Biol. 2004 Jul;76(1):42-7
15075353
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1966-71
12569171
FASEB J. 2006 Oct;20(12):2112-4
16935932
FEMS Immunol Med Microbiol. 2002 Jan 14;32(2):133-40
11821235
J Immunol. 2001 Aug 15;167(4):2202-8
11490006
J Exp Med. 1990 Feb 1;171(2):465-75
2303781