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Katherine E. Cole^*, Christine A. Strick^*, Timothy J. Paradis, Kevin T. Ogborne^*, Marcel Loetscher, Ronald P. Gladue, Wen Lin^*, James G. Boyd^*, Bernhard Moser, Douglas E. Wood^*, Barbara G. Sahagan^*, and Kuldeep Neote^*

From the ^* Department of Molecular Sciences and the Department of Immunology, Central Research Division, Pfizer Inc., Groton, Connecticut 06340; and the Theodor Kocher Institute, University of Bern, CH-300-ern-9, Switzerland

Chemokines are essential mediators of normal leukocyte trafficking as well as of leukocyte recruitment during inflammation. We describe here a novel non-ELR CXC chemokine identified through sequence analysis of cDNAs derived from cytokine-activated primary human astrocytes. This novel chemokine, referred to as I-TAC (interferon-inducible T cell alpha chemoattractant), is regulated by interferon (IFN) and has potent chemoattractant activity for interleukin (IL)-2–activated T cells, but not for freshly isolated unstimulated T cells, neutrophils, or monocytes. I-TAC interacts selectively with CXCR3, which is the receptor for two other IFN-inducible chemokines, the IFN-–inducible 10-kD protein (IP-10) and IFN-– induced human monokine (HuMig), but with a significantly higher affinity. In addition, higher potency and efficacy of I-TAC over IP-10 and HuMig is demonstrated by transient mobilization of intracellular calcium as well as chemotactic migration in both activated T cells and transfected cell lines expressing CXCR3. Stimulation of astrocytes with IFN- and IL-1 together results in an 400,000-fold increase in I-TAC mRNA expression, whereas stimulating monocytes with either of the cytokines alone or in combination results in only a 100-fold increase in the level of I-TAC transcript. Moderate expression is also observed in pancreas, lung, thymus, and spleen. The high level of expression in IFN- and IL-1–stimulated astrocytes suggests that I-TAC could be a major chemoattractant for effector T cells involved in the pathophysiology of neuroinflammatory disorders, although I-TAC may also play a role in the migration of activated T cells during IFN-dominated immune responses.

Key Words: neuroinflammation • astrocytes • calcium • signaling • brain

Abbreviations used: EAE, experimental autoimmune encephalomyelitis; ELR, Glu-Leu-Arg; HEK, human embryonic kidney; HuMig, IFN-–induced human monokine; IP-10, IFN-–inducible 10-kD protein; I-TAC, IFN-inducible T cell alpha chemoattractant; MCP, monocyte chemotactic protein; SDF, stromal cell–derived factor.

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