Blood 2003 May 15
Smit MJ, Verdijk P, Van Der Raaij-Helmer EM, Navis M, Hensbergen PJ, Leurs R, Tensen CP.
Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
The chemokines CXCL9, 10 and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T-cells.
These IFN-gamma induced chemokines, are thought to be crucial in directing activated T-cells to sites of inflammation.
As such, they play an important role in several chronic inflammatory diseases, including ulcerative colitis, multiple sclerosis, artherosclerosis and delayed type hypersensitivity reactions of the skin.
In this study, we first demonstrate that in COS-7 cells heterologously expressing CXCR3, CXCL11 is a potent activator of the pertussis toxin sensitive (PTX) p44/p42 MAPK and Akt/PI-3 kinase pathways.
Next, we show that these signal transduction pathways are also operative and PTX sensitive in primary human T-cells expressing CXCR3.
Importantly, abrogation of these signaling cascades by specific inhibitors did not block the migration of T-cells towards CXCR3 ligands, suggesting that MAPK and Akt activation is not crucial for CXCR3-mediated chemotaxis of T-cells.
Finally, we demonstrate that CXCR3 targeting chemokines control T-cell migration via PTX sensitive, phospholipase C pathways and phosphatidylinositol kinases other than class I PI3-Kgamma.