Streptococcus Pneumoniae-induced P38 MAPK and NF-kB dependent COX-2 expression in human lung epithelium

Introduction: S. pneumoniae is a major cause of community-acquired pneumonia and death due to infectious diseases in industrialized countries. Lung airway and alveolar epithelial cells comprise an important barrier against airborne pathogens. Cyclooxygenase (COX) derived prostaglandins like prostaglandin E2 (PGE2) are considered as important regulators of lung function. Herein we tested the hypothesis that pneumococci induced COX-2 dependent PGE2 production in pulmonary epithelial cells.

Methods: BEAS-2B cells, Western blot, ELISA, chromatin-immunoprecipitation, EMSA, mice pneumonia model.

Results: Pneumococci infected human pulmonary epithelial BEAS-2B cells released PGE2. 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 IkBa and DNA-binding of NF-kB. A specific peptide inhibitor of the IkBa kinase complex blocked pneumococci-induced PGE2 release and COX-2 expression. In addition, we noted activation of p38 MAP kinase and cJun-NH2-terminal kinase (JNK) in pneumococci infected cells. PGE2 release and COX-2 expression was reduced by p38 MAP kinase-inhibitor SB202190 but not by JNK-inhibitor SP600125. We analyzed interaction of kinase pathways and NF-kB activation: dominant negative mutants of p38 MAP kinase isoforms a, b2, g, and d blocked S. pneumoniae-induced NF-kB activation. In addition, recruitment of NF-kB subunit p65/RelA and RNA polymerase II to the cox2 promoter depended on p38 MAP kinase but not on JNK activity.

In summary, p38 MAP kinase and NF-kB controlled COX-2 expression and subsequent PGE2 release by lung epithelial cells may contribute significantly to the host response in pneumococcal pneumonia.

The German Federal Ministry of Education and Research, Competence Network CAPNETZ supported this study.