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Yersinia enterocolitica Adhesin A Induces Production of Interleukin-8 in Epithelial Cells

Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Tübingen, Tübingen, Germany,¹ Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, and Helsinki University Central Hospital Laboratory Diagnostics, Helsinki, Finland²

Received 18 May 2004/ Returned for modification 29 June 2004/ Accepted 24 August 2004

The major invasive factor of Yersinia enterocolitica, the invasin (Inv) protein, induces proinflammatory host cell responses, including interleukin-8 (IL-8) secretion from human epithelial cells, by engagement of ß1 integrins. The Inv-triggered ß1 integrin signaling involves the small GTPase Rac; the activation of MAP kinases, such as p38, MEK1, and JNK; and the activation of the transcription factor NF-B. In the present study, we demonstrate that Y. enterocolitica YadA, which is a major adhesin of Y. enterocolitica with pleiotropic virulence effects, induces IL-8 secretion in epithelial cells. The abilites of YadA and Inv to promote adhesion to and invasion of HeLa cells and to induce IL-8 production by the cells were investigated by expression of YadA and Inv in Escherichia coli. While YadA mediates efficacious adhesion to HeLa cells, it mediates marginal invasion compared with Inv. Both YadA and Inv trigger comparable levels of IL-8 production. Conformational changes of the YadA head domain by mutation of NSVAIG-S motifs, which abolish collagen binding, also abolish adhesion of Yersinia to HeLa cells and YadA-mediated IL-8 secretion. Furthermore, experiments in which blocking antibodies against ß1 integrins were used demonstrate that ß1 integrins are crucial for YadA-mediated IL-8 secretion. Inhibitor studies demonstrate the involvement of small GTPases and MAP kinases, such as p38, MEK1, and JNK, indicating that ß1 integrin-dependent signaling mediated by Inv or YadA involves similar signaling pathways. These data present YadA, in addition to Inv, YopB, and Yersinia lipopolysaccharide, as a further inducer of proinflammatory molecules by which Y. enterocolitica might promote inflammatory tissue reactions.

Editor: J. B. Bliska

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