The tyrosine kinase Pyk2 mediated lipopolysaccharide-induced IL-8 expression in human endothelial cells

Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210, USA.
The Journal of Immunology (Impact Factor: 5.36). 05/2008; 180(8):5636-44. DOI: 10.4049/jimmunol.180.8.5636
Source: PubMed

ABSTRACT 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.

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Available from: Magali Cucchiarini, Jul 30, 2015
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    • "Pyk2 functions by coupling several receptors (including integrin and chemokine receptors) with a variety of downstream effectors, thus regulating various functions such as cell adhesion, migration, proliferation and survival (Avraham et al., 2000; Di Cioccio et al., 2004; Liu et al., 1997; Zheng et al., 1998). We and others have shown that Pyk2 tyrosine phosphorylation could be closely associated with inflammatory processes in various cell types (Anand et al., 2008; Di Cioccio et al., 2004; Liu et al., 1997; Yamasaki et al., 2001). In the present study, we questioned whether Pyk2 was involved in the MCP-1 production that we observed upon LPS stimulation. "
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