Expression and agonist responsiveness of CXCR3 variants in human T lymphocytes.
The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 are involved in variety of inflammatory disorders including multiple sclerosis, rheumatoid arthritis, psoriasis and sarcoidosis. Two alternatively spliced variants of the human CXCR3-A receptor have been described, termed CXCR3-B and CXCR3-alt. Human CXCR3-B binds CXCL9, CXCL10, CXCL11 as well as an additional ligand CXCL4. In contrast, CXCR3-alt only binds CXCL11. We report that CXCL4 induces intracellular calcium mobilization as well as Akt and p44/p42 extracellular signal-regulated kinase phosphorylation, in activated human T lymphocytes. These responses have similar concentration dependence and time-courses to those induced by established CXCR3 agonists. Moreover, phosphorylation of Akt and p44/p42 is inhibited by pertussis toxin, suggesting coupling to Gα(i) protein. Surprisingly, and in contrast with the other CXCR3 agonists, stimulation of T lymphocytes with CXCL4 failed to elicit migratory responses and did not lead to loss of surface CXCR3 expression. Taken together, our findings show that, although CXCL4 is coupled to downstream biochemical machinery, its role in T cells is probably distinct from that of CXCR3-A agonists.
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, UK.
Anna
A
Korniejewska
Andrew J
AJ
McKnight
Zoë
Z
Johnson
Malcolm L
ML
Watson
Stephen G
SG
Ward
D000081:Acetamides / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000494:pharmacology; D054371:Chemokine CXCL11 / Q000235:genetics / Q000494:pharmacology; D054370:Chemokine CXCL9 / Q000235:genetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010978:Platelet Factor 4 / Q000235:genetics / Q000494:pharmacology; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D054367:Receptors, CXCR3 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D000081:Acetamides; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; C501976:NBI-74330; D020033:Protein Isoforms; D011743:Pyrimidines; D054367:Receptors, CXCR3; D011994:Recombinant Proteins; D010978:Platelet Factor 4; D037342:Pertussis Toxin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium
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