Streptococcus pneumoniae induced p38 MAPK- and NF-kappaB-dependent COX-2 expression in human lung epithelium.
Streptococcus pneumoniae is a major cause of community-acquired pneumonia and death from infectious diseases in industrialized countries. Lung airway and alveolar epithelial cells comprise an important barrier against airborne pathogens. Cyclooxygenase (COX)-derived prostaglandins, such as PGE(2), are considered to be important regulators of lung function. Herein, we tested the hypothesis that pneumococci induced COX-2-dependent PGE(2) production in pulmonary epithelial cells. Pneumococci-infected human pulmonary epithelial BEAS-2B cells released PGE(2). Expression of COX-2 but not COX-1 was dose and time dependently increased in S. pneumoniae-infected BEAS-2B cells as well as in lungs of mice with pneumococcal pneumonia. S. pneumoniae induced degradation of IkappaBalpha and DNA binding of NF-kappaB. A specific peptide inhibitor of the IkappaBalpha kinase complex blocked pneumococci-induced PGE(2) release and COX-2 expression. In addition, we noted activation of p38 MAPK and JNK in pneumococci-infected BEAS-2B cells. PGE(2) release and COX-2 expression were reduced by p38 MAPK inhibitor SB-202190 but not by JNK inhibitor SP-600125. We analyzed interaction of kinase pathways and NF-kappaB activation: dominant-negative mutants of p38 MAPK isoforms alpha, beta(2), gamma, and delta blocked S. pneumoniae-induced NF-kappaB activation. In addition, recruitment of NF-kappaB subunit p65/RelA and RNA polymerase II to the cox2 promoter depended on p38 MAPK but not on JNK activity. In summary, p38 MAPK- and NF-kappaB-controlled COX-2 expression and subsequent PGE(2) release by lung epithelial cells may contribute significantly to the host response in pneumococcal pneumonia.
N'Guessan
Philippe Dje
PD
Dept. of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Hippenstiel
Stefan
S
Etouem
Mirabelle O
MO
Zahlten
Janine
J
Beermann
Wiebke
W
Lindner
David
D
Opitz
Bastian
B
Witzenrath
Martin
M
Rosseau
Simone
S
Suttorp
Norbert
N
Schmeck
Bernd
B
D001483:Base Sequence; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics*; D017931:DNA Primers; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism*; D010957:Plasmids; D011008:Pneumococcal Infections / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000201:enzymology*; D013296:Streptococcus pneumoniae / Q000502:physiology*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics
D017931:DNA Primers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; C465539:SB202494; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole