Streptococcus pneumoniae-induced p38 MAPK-dependent phosphorylation of RelA at the interleukin-8 promotor.
Streptococcus pneumoniae is the major cause of community-acquired pneumonia and one of the most common causes of death by infectious disease in industrialized countries. Little is known concerning the mechanisms of target cell activation in this disease. The present study shows that NF-kappaB and p38 MAPK signaling pathways contribute to chemokine synthesis by lung epithelial cells in response to pneumococci. In infected lungs of mice pneumococci stimulate expression of the interleukin (IL)-8 homolog keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor, as well as activate p38 MAPK. Human bronchial epithelium was chosen as a cellular model, because it establishes the first barrier against pathogens, and little is known about its function in innate immunity. Pneumococci infection induces expression of IL-8 and granulocyte-macrophage colony-stimulating factor as well as activation of p38 MAPK in human bronchial epithelial cells (BEAS-2B). Inhibition of p38 MAPK activity by SB202190 and SB203580 blocks pneumococci-induced cytokine release. In mouse lungs in vivo as well as in cultured cells, pneumococci activate NF-kappaBinanIkappaB kinase-dependent manner. Inhibition of p38 MAPK by chemical inhibitors or by RNA interference targeting p38alpha reduces pneumococci-induced NF-kappaB-dependent gene transcription. Blockade of p38 activity did not affect inducible nuclear translocation and recruitment of NF-kappaB/RelA to the IL-8 promotor but did reduce the level of phosphorylated RelA (serine 536) at IL-8 promotor and inhibited pneumococci-mediated recruitment of RNA polymerase II to IL-8 promotor. Thus, p38 MAPK contributes to pneumococci-induced chemokine transcription by modulating p65 NF-kappaB-mediated transactivation.
Department of Internal Medicine/Infectious Diseases, Charité, University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Bernd
B
Schmeck
Janine
J
Zahlten
Kerstin
K
Moog
Vincent
V
van Laak
Sylvia
S
Huber
Andreas C
AC
Hocke
Bastian
B
Opitz
Elke
E
Hoffmann
Michael
M
Kracht
Jens
J
Zerrahn
Sven
S
Hammerschmidt
Simone
S
Rosseau
Norbert
N
Suttorp
Stefan
S
Hippenstiel
D000818:Animals; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000382:microbiology; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011014:Pneumonia / Q000382:microbiology / Q000473:pathology; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D012319:RNA Polymerase II / Q000737:chemistry; D018075:RNA, Complementary / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000201:enzymology*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018925:Chemokines; D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016209:Interleukin-8; D011725:Pyridines; D018075:RNA, Complementary; D012694:Serine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases; D012319:RNA Polymerase II; C093642:SB 203580