Streptococcus pneumoniaeinduced p38 MAPK- and NF-κB-dependent COX-2 expression in human lung epithelium

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Abstract
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 PGE2, are considered to be important regulators of lung function. Herein, we tested the hypothesis that pneumococci induced COX-2-dependent PGE2 production in pulmonary epithelial cells. 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 IκBα and DNA binding of NF-κB. A specific peptide inhibitor of the IκBα kinase complex blocked pneumococci-induced PGE2 release and COX-2 expression. In addition, we noted activation of p38 MAPK and JNK in pneumococci-infected BEAS-2B cells. PGE2 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-κB activation: dominant-negative mutants of p38 MAPK isoforms α, β2, γ, and δ blocked S. pneumoniae-induced NF-κB activation. In addition, recruitment of NF-κB 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-κB-controlled COX-2 expression and subsequent PGE2 release by lung epithelial cells may contribute significantly to the host response in pneumococcal pneumonia.