Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3.
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-gamma-inducible 10-kD protein (IP-10) and IFN-gamma- 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-gamma and IL-1 together results in an approximately 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.
Cole
K E
KE
Department of Molecular Sciences, Central Research Division, Pfizer Inc., Groton, Connecticut 06340, USA.
Strick
C A
CA
Paradis
T J
TJ
Ogborne
K T
KT
Loetscher
M
M
Gladue
R P
RP
Lin
W
W
Boyd
J G
JG
Moser
B
B
Wood
D E
DE
Sahagan
B G
BG
Neote
K
K
D000595:Amino Acid Sequence; D001253:Astrocytes; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D002894:Chromosomes, Human, Pair 4; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D003888:Desensitization, Immunologic; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D018076:DNA, Complementary; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D007371:Interferon-gamma; D002118:Calcium