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The Tyrosine Kinase Pyk2 Mediates Lipopolysaccharide-Induced IL-8 Expression in Human Endothelial Cells¹

Appakkudal R. Anand^*, Magali Cucchiarini, Ernest F. Terwilliger and Ramesh K. Ganju^2,*

^* Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210; and Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115

Secretion of proinflammatory cytokines by LPS activated endothelial cells contributes substantially to the pathogenesis of sepsis. However, the mechanism involved in this process is not well understood. In the present study, we determined the role of a nonreceptor proline-rich tyrosine kinase, Pyk2, in LPS-induced IL-8 (CXCL8) production in endothelial cells. First, we observed a marked activation of Pyk2 in response to LPS. Furthermore, inhibition of Pyk2 activity in these cells by transduction with the catalytically inactive Pyk2 mutant, transfection with Pyk2-specific small interfering RNA, or treatment with Tyrphostin A9 significantly blocked LPS-induced IL-8 production. The supernatants of LPS-stimulated cells exhibiting attenuated Pyk2 activity blocked transendothelial neutrophil migration in comparison to the supernatants of LPS-treated controls, thus confirming the inhibition of functional IL-8 production. Investigations into the molecular mechanism of this pathway revealed that LPS activates Pyk2 leading to IL-8 production through the TLR4. In addition, we identified the p38 MAPK pathway to be a critical step downstream of Pyk2 during LPS-induced IL-8 production. Taken together, these results demonstrate a novel role for Pyk2 in LPS-induced IL-8 production in endothelial cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported in part by Grants AI49140 and CA109527 from the National Institutes of Health (to R.K.G.).

² Address correspondence and reprint requests to Dr. Ramesh K. Ganju, Department of Pathology, Ohio State University Medical Center, 1645 Neil Avenue, 166 Hamilton Hall, Columbus, OH 43210. E-mail address: Ramesh.Ganju{at}osumc.edu

³ Abbreviations used in this paper: FAK, focal adhesion kinase; siRNA, small interfering RNA; AAV, adeno-associated virus; EBM, endothelial basal medium; TEM, transendothelial migration; β-Gal, β-galactosidase.

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