Pneumolysin-Mediated Expression of beta-Defensin 2 Is Coordinated by p38 MAP Kinase-MKP1 in Human Airway Cells

Abstract

Antimicrobial peptides act as important innate immune defense mediators against invading microbes such as Streptococcus pneumoniae. Among a number of antimicrobial peptides, beta-defensin 2 (BD2) has strong antimicrobial activity against S. pneumoniae. However, little is known about the molecular signaling mechanisms leading to the BD2 expression. Here, we report that BD2 is strongly induced by S. pneumoniae in human airway cells including human middle-ear cells. Among diverse pneumococcal virulence factors, pneumolysin is required for inducing BD2 whose expression is under the control of p38 mitogen-activated protein kinase (MAPK). Pneumolysin also selectively regulates the expression of MAPK phosphatase 1 (MKP1), which inhibits the p38 signaling pathway, thereby leading to upregulation of BD2 to mount an effective defense against S. pneumoniae infection. These results provide novel insights into the molecular mechanisms underlying the coordinative regulation of BD2 expression via p38-MKP1 in the pathogenesis of airway infectious diseases.