Induction of human β-defensin-2 in pulmonary epithelial cells byLegionella pneumophila: involvement of TLR2 and TLR5, p38 MAPK, JNK, NF-κB, and AP-1

Abstract

Legionella pneumophila is an important causative agent of severe pneumonia in humans. Human alveolar epithelium is an effective barrier for inhaled microorganisms and actively participates in the initiation of innate host defense. Induction of antimicrobial peptide human β-defensin-2 (hBD-2) by various stimuli in epithelial cells has been reported. However, the mechanisms by which bacterial infections enhance hBD-2 expression remain poorly understood. In this study, we investigated the effect of the pulmonary pathogen L. pneumophila on induction of hBD-2 in human pulmonary epithelial cells. Infection with L. pneumophila markedly increased hBD-2 production, and the response was attenuated in Toll-like receptor (TLR) 2 and TLR5 transient knockdown cells. Furthermore, pretreatment with SB-202190 (an inhibitor of p38 MAPK) and JNK II (an inhibitor of c-Jun NH2-terminal kinase), but not U0126 (an inhibitor of ERK), reduced L. pneumophila-induced hBD-2 release in A549 cells. L. pneumophila-induced hBD-2 liberation was mediated via recruitment of NF-κB and AP-1 to the hBD-2 gene promoter. Additionally, we showed that exo- and endogenous hBD-2 elicited a strong antimicrobial effect towards L. pneumophila. Together, these results suggest that L. pneumophila induces hBD-2 release in A549 cells, and the induction seems to be mediated through TLR2 and TLR5 as well as activation of p38 MAPK, JNK, NF-κB, and AP-1.

Zinc induces LPS-mediated upregulation of HBD-2 via ERK1/2 and p38MAPK signaling pathways in human prostate epithelial cells

“…HBD-2 expression has been shown to be controlled by p38 MAPK in pulmonary epithelial cells (Scharf et al 2010). ERK1/2 also regulates HBD-2 expression in middle ear epithelial cells (Moon et al 2002).…”

MAPK/AP-1 activation mediates TLR2 agonist-induced SPLUNC1 expression in human lung epithelial cells

“…Inhibition of NF-κB partly suppressed Mycoplasma pneumoniae -induced SPLUNC1 expression whereas over-expression of IKKβ significantly increased SPLUNC1 expression in epithelial cells (Chu et al, 2010). TLR2 activation has been shown to induce MAPK/AP-1 signaling in lung epithelial cells (Scharf et al, 2010; Schmeck et al, 2006). Our data suggest that TLR2 activation following Pam 3 CSK 4 stimulation increases SPLUNC1 in part through MAPK/AP-1 signaling.…”

“…One of the downstream events following MAPK activation is activation and nuclear translocation of transcription factor c-Jun, a member of the activator protein-1 (AP-1) family. Activation of TLRs including TLR2 has been shown to activate MAPK/AP-1 signaling in airway epithelial cells, which may promote the production of inflammatory mediators and host defense proteins such as β-defensin-2 (Scharf et al, 2010; Schmeck et al, 2006). However, the role of TLR2-mediated MAPK/AP-1 activation in SPLUNC1 regulation remains to be determined.…”

Defensins and Other Antimicrobial Peptides and a Role of Neutrophil Protein-Synthesing Function Disorders for Pathogenesis of Respiratory Diseases

“…Хорошо изучена обусловленная участием HD противомикробная за-щита против некоторых опасных бактерий и виру-сов, вызывающих пневмонии и другие заболевания дыхательного аппарата. ПМП защищают человека в т. ч. от инфекции Legionella pneumophila [38], S. pneumoniaе [39], Klebsiella pneumoniae [40], Acinetobacter baumannii, P. aeruginosa [14], E. faecalis, S. aureus, E. coli, P. mirabilis [41,42], Candida spp. [7], Bacteroides fragilis [36], многих ДНК-и РНК-содержащих виру-сов (гриппа, везикулярного стоматита, герпеса 2-го типа, цитомегаловируса, папилломавируса, аденови-руса, вируса иммунодефицита человека) [5,[43][44][45].…”