Abstract
Streptococcus pneumoniae is the major pathogen of community-acquired pneumonia. The respiratory epithelium constitutes the first line of defense against invading lung pathogens, including pneumococci. We analyzed the involvement of Toll-like receptors (TLR) and Rho-GTPase signaling in the activation of human lung epithelial cells by pneumococci. S. pneumoniae induced release of interleukin-8 (IL-8) by human bronchial epithelial cell line BEAS-2B. Specific inhibition of Rac1 by Nsc23766 or a dominant-negative mutant of Rac1 strongly reduced cytokine release. In addition, pneumococci-related cell activation (IL-8 release, NF-kappaB-activation) depended on MyD88, phosphatidylinositol 3-kinase, and Cdc42 but not on RhoA. Pneumococci enhanced TLR1 and TLR2 mRNA expression in BEAS-2B cells, whereas TLR4 and TLR6 expression was constitutively high. TLR1 and 2 synergistically recognized pneumococci in cotransfection experiments. TLR4, TLR6, LPS-binding protein, and CD14 seem not to be involved in pneumococci-dependent cell activation. At the IL-8 gene promoter, recruitment of phosphorylated NF-kappaB subunit p65 was blocked by inhibition of Rac1, whereas binding of the phosphorylated activator protein-1 subunit c-Jun to the promoter was not diminished. In summary, these results suggest that S. pneumoniae activate human epithelial cells by TLR1/2 and a phosphatidylinositol 3-kinase- and Rac1-dependent NF-kappaB-recruitment to the IL-8 promoter.
Original language | English |
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Pages (from-to) | L730-L737 |
Journal | American journal of physiology. Lung cellular and molecular physiology |
Volume | 290 |
Issue number | 4 |
DOIs | |
Publication status | Published - Apr 2006 |
Keywords
- Adaptor Proteins, Signal Transducing
- Bacterial Outer Membrane Proteins
- Bacterial Proteins
- Bronchi
- Cell Line
- Epithelial Cells
- Humans
- Interleukin-8
- Myeloid Differentiation Factor 88
- NF-kappa B
- Phosphatidylinositol 3-Kinases
- Phosphorylation
- Promoter Regions, Genetic
- Signal Transduction
- Streptococcus pneumoniae
- Streptolysins
- Toll-Like Receptor 1
- Toll-Like Receptor 2
- Toll-Like Receptor 4
- Transcription Factor RelA
- Transcription, Genetic
- rac1 GTP-Binding Protein
- rho GTP-Binding Proteins