The JAK2-Akt-glycogen synthase kinase-3β signaling pathway is involved             in toll-like receptor 2-induced monocyte chemoattractant protein-1 regulation.
Monocyte chemoattractant protein-1 (MCP-1) is an essential cytokine for the migration of monocytes into vessels, and is also involved in the pathogenesis of atherosclerosis. In this study, we investigated the importance of janus kinase 2 (JAK2) and the function of the Akt and glycogen synthase kinase-3β (GSK3β) pathway in toll-like receptor (TLR2)-mediated MCP-1 expression. The TLR2 agonist, Pam3CSK4, induced MCP-1 expression in the Raw264.7 cell line. The induction of MCP-1 was seen in the bone marrow-derived macrophages of wild-type mice but not in TLR2 knockout mice. The TLR2-mediated MCP-1 induction was myeloid differentiation primary response gene 88 (MyD88)-independent. By contrast, the inactivation of JAK2 attenuated TLR2-mediated MCP-1 expression. The JAK inhibitor suppressed the phosphorylation of GSK3β as well as Akt by Pam3CSK4 stimulation. While the inactivation of Akt by LY294002 suppressed TLR2-mediated MCP-1 induction, the inactivation of GSK3β by LiCl potentiated TLR2-mediated MCP-1 induction. Furthermore, Akt inhibitor suppressed TLR2-mediated phosphorylation of GSK3β. Taken together, these results suggest that a MyD88-independent pathway exists in TLR2 signaling; the JAK2-Akt-GSK3β pathway is a novel MyD88-independent pathway for MCP-1 induction.
Department of Biochemistry and Molecular Biology, Aging-associated                     Vascular Disease Research Center, 210 Main Building, College of Medicine,                     Yeungnam University, Daegu 705-802, Republic of Korea.
Dae-Weon
DW
Park
Hyung-Kyoung
HK
Lee
Tae-Whal
TW
Jeong
Jin-Sik
JS
Kim
Yoe-Sik
YS
Bae
Byung-Rho
BR
Chin
Suk-Hwan
SH
Baek
D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055666:Lipopeptides / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D018932:Chemokine CCL2; D002867:Chromones; D055666:Lipopeptides; D009025:Morpholines; D053594:Myeloid Differentiation Factor 88; C560312:Pam2CSK4 lipopeptide; D051195:Toll-Like Receptor 2; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D053614:Janus Kinase 2; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride