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Pneumococci induced TLR- and Rac1-dependent NF-B-recruitment to the IL-8 promoter in lung epithelial cells

Departments of ¹Internal Medicine/Infectious Diseases and ²Paradontology, Charité—Universitätsmedizin Berlin, Berlin; ³Research Center for Infectious Diseases, University of Würzburg, Würzburg, Germany; ⁴Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, United Kingdom; and ⁵Institute of Pharmacology, Medizinische Hochschule Hannover, Hannover, Germany

Submitted 23 June 2005 ; accepted in final form 11 November 2005

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-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, 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-B 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-B-recruitment to the IL-8 promoter.

phosphatidylinositol 3-kinase; Rac1; p65/RelA; BEAS-2B cells; Toll-like receptor; interleukin-8; nuclear factor-B

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