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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2002-12-3945.
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Blood, 15 September 2003, Vol. 102, No. 6, pp. 1959-1965
CHEMOKINES
CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C–dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3 kinase
Martine J. Smit,
Pauline Verdijk,
Elisabeth M. H. van der Raaij-Helmer,
Marjon Navis,
Paul J. Hensbergen,
Rob Leurs, and
Cornelis P. Tensen
From the Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Division of Medicinal Chemistry, Amsterdam, The Netherlands; and Department of Dermatology, Leiden University Medical Center, Leiden, 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 interferon  (IFN)–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 (PTX)–sensitive p44/p42 mitogen-activated protein kinase (MAPK) and Akt/phosphatidylinositol 3 kinase (PI3K) 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 toward 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 PI3K.
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