Gene interactions and pathways from curated databases and text-mining
Mol Immunol 2009, PMID: 18954908

LPS-induced MCP-1 expression in human microvascular endothelial cells is mediated by the tyrosine kinase, Pyk2 via the p38 MAPK/NF-kappaB-dependent pathway.

Anand, Appakkudal R; Bradley, Ritu; Ganju, Ramesh K

Bacterial endotoxin (lipopolysaccharide or LPS) has potent pro-inflammatory properties and acts on many cell types including endothelial cells. Secretion of the CC chemokine, MCP-1 (CCL2) by LPS-activated endothelial cells contributes substantially to the pathogenesis of sepsis. However, the mechanism involved in LPS-induced MCP-1 production in endothelial cells is not well understood. Using human microvascular endothelial cells (HMVEC), we analyzed the involvement of the non-receptor tyrosine kinase, Pyk2, in LPS-mediated MCP-1 production. There was a marked activation of the non-receptor tyrosine kinase, Pyk2, in response to LPS. Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9 significantly attenuated LPS-induced Pyk2 tyrosine phosphorylation, p38 MAP kinase (MAPK) activation, NF-kappaB activation, and MCP-1 expression. Furthermore, specific inactivation of Pyk2 activity by transducing microvascular endothelial cells with catalytically inactive Pyk2 mutant (AAV-Pyk2MT) or Pyk2-specific siRNA significantly blocked LPS-induced MCP-1 production. The supernatants of these LPS-stimulated cells with attenuated Pyk2 activity demonstrated decreased trans-endothelial monocyte migration in comparison to LPS-treated controls, thus confirming the inhibition of functional MCP-1 production. In summary, our data suggest a critical role for the Pyk2 mediated pathway involving p38 MAP kinase and NF-kappaB in LPS-induced MCP-1 production in human microvascular endothelial cells.

Diseases/Pathways annotated by Medline MESH: MAP Kinase Signaling System, Sepsis
Document information provided by NCBI PubMed

Text Mining Data

MCP-1 → LPS: " LPS induced MCP-1 expression in human microvascular endothelial cells is mediated by the tyrosine kinase, Pyk2 via the p38 MAPK/NF-kappaB dependent pathway "

MCP-1 → LPS: " However, the mechanism involved in LPS induced MCP-1 production in endothelial cells is not well understood "

MCP-1 → LPS: " Using human microvascular endothelial cells ( HMVEC ), we analyzed the involvement of the non-receptor tyrosine kinase, Pyk2, in LPS mediated MCP-1 production "

MCP-1 → LPS: " Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9 significantly attenuated LPS induced Pyk2 tyrosine phosphorylation, p38 MAP kinase ( MAPK ) activation, NF-kappaB activation, and MCP-1 expression "

MCP-1 → Pyk2: " Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9 significantly attenuated LPS induced Pyk2 tyrosine phosphorylation, p38 MAP kinase ( MAPK ) activation, NF-kappaB activation, and MCP-1 expression "

MAP kinase ( MAPK ) → LPS: " Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9 significantly attenuated LPS induced Pyk2 tyrosine phosphorylation, p38 MAP kinase ( MAPK ) activation, NF-kappaB activation, and MCP-1 expression "

MAP kinase ( MAPK ) → Pyk2: " Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9 significantly attenuated LPS induced Pyk2 tyrosine phosphorylation, p38 MAP kinase ( MAPK ) activation, NF-kappaB activation, and MCP-1 expression "

NF-kappaB → LPS: " Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9 significantly attenuated LPS induced Pyk2 tyrosine phosphorylation, p38 MAP kinase ( MAPK ) activation, NF-kappaB activation, and MCP-1 expression "

NF-kappaB → Pyk2: " Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9 significantly attenuated LPS induced Pyk2 tyrosine phosphorylation, p38 MAP kinase ( MAPK ) activation, NF-kappaB activation, and MCP-1 expression "

Pyk2 → LPS: " Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9 significantly attenuated LPS induced Pyk2 tyrosine phosphorylation, p38 MAP kinase ( MAPK ) activation, NF-kappaB activation, and MCP-1 expression "

MCP-1 → LPS: " Furthermore, specific inactivation of Pyk2 activity by transducing microvascular endothelial cells with catalytically inactive Pyk2 mutant ( AAV-Pyk2MT ) or Pyk2-specific siRNA significantly blocked LPS induced MCP-1 production "

MCP-1 → LPS: " In summary, our data suggest a critical role for the Pyk2 mediated pathway involving p38 MAP kinase and NF-kappaB in LPS induced MCP-1 production in human microvascular endothelial cells "

Manually curated Databases

No curated data.