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B-recruitment to the IL-8 promoter in lung epithelial cells
1 Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charite - Universitaetsmedizin Berlin, Berlin, Germany
2 Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charite - Universitaetsmedizin Berlin, Berlin, Germany; Department of Paradontology, Charite - Universitaetsmedizin Berlin, Berlin, Germany
3 Research Center for Infectious Diseases, University of Wuerzburg, Wuerzburg, Germany
4 Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glagow, Glagow, United Kingdom
5 Institute of Pharmacology, Medizinische Hochschule Hannover, Hannover, Germany
* To whom correspondence should be addressed. E-mail: Stefan.Hippenstiel{at}charite.de.
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 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-
B-activation) depended on MyD88, phosphatidylinositol 3-kinase and Cdc42 but not on RhoA. Pneumococci enhanced TLR1 and TLR2 mRNA-expression in BEAS-2B cells, while TLR4 and TLR 6-expression was constitutively high. TLR1 and 2 synergistically recognized pneumococci in co-transfection experiments. TLR4, TLR6, LBP, and CD14 seem not to be involved in pneumococci-dependent cell activation. At the IL-8 gene promoter, recruitment of phosphorylated NF-B-subunit p65 was blocked by inhibition of Rac1, whereas binding of the phosphorylated AP-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 Pi3K- and Rac1-dependent NF-B-recruitment to the IL-8 promoter.
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