Streptococcus pneumoniae induced p38 MAPK- and NF-kappaB-dependent COX-2 expression in human lung epithelium

• Published in: American journal of physiology. Lung cellular and molecular physiology 2006-06, Vol.290 (6), p.L1131-L1138
• Main Authors: N'Guessan, Philippe Dje, Hippenstiel, Stefan, Etouem, Mirabelle O, Zahlten, Janine, Beermann, Wiebke, Lindner, David, Opitz, Bastian, Witzenrath, Martin, Rosseau, Simone, Suttorp, Norbert, Schmeck, Bernd
• Format: Article
• Language: English
• Subjects: Base Sequence; Cell Line; Cyclooxygenase 2 - genetics; DNA Primers; Enzyme Induction; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Humans; Imidazoles - pharmacology; Lung - cytology; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - biosynthesis; p38 Mitogen-Activated Protein Kinases - genetics; Plasmids; Pneumococcal Infections - physiopathology; Pyridines - pharmacology; Respiratory Mucosa - enzymology; Streptococcus pneumoniae - physiology; Transfection
• ISSN: 1040-0605

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.