Identification of CCR6, the Specific Receptor for a Novel Lymphocyte-directed CC Chemokine LARC

• Published in: The Journal of biological chemistry 1997-06, Vol.272 (23), p.14893-14898
• Main Authors: Baba, M, Imai, T, Nishimura, M, Kakizaki, M, Takagi, S, Hieshima, K, Nomiyama, H, Yoshie, O
• Format: Article
• Language: English
• Subjects: AIDS/HIV; B-Lymphocytes - physiology; Binding, Competitive; Calcium - metabolism; CD4-Positive T-Lymphocytes - physiology; CD8-Positive T-Lymphocytes - physiology; Cell Line; Chemokine CCL20; Chemokines - metabolism; Chemokines - pharmacology; Chemokines, CC; Chemotaxis; Cloning, Molecular; Hematopoietic Stem Cells; Humans; Kidney; Kinetics; Liver - metabolism; Lymphocytes - physiology; Macrophage Inflammatory Proteins; Receptors, CCR6; Receptors, Chemokine; Receptors, Cytokine - biosynthesis; Receptors, Cytokine - physiology; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; RNA, Messenger - biosynthesis; Transcription, Genetic; Transfection; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.23.14893

L iver and a ctivation- r egulated c hemokine (LARC) is a recently identified CC chemokine that is expressed mainly in the liver. LARC functions as a selective chemoattractant for lymphocytes that express a class of receptors specifically binding to LARC with high affinity. To identifiy the receptor for LARC, we examined LARC-induced calcium mobilization in cells stably expressing five CC chemokine receptors (CCR1-CCR5) and five orphan seven-transmembrane receptors. LARC specifically induced calcium flux in K562 cells as well as 293/EBNA-1 cells stably expressing an orphan receptor GPR-CY4. LARC induced migration in 293/EBNA-1 cells stably expressing GPR-CY4 with a bi-modal dose-response curve. LARC fused with secreted alkaline phosphatase (LARC-SEAP) bound specifically to Raji cells stably expressing GPR-CY4 with a K d of 0.9 n m . Only LARC but not five other CC chemokines (MCP-1, RANTES, MIP-1α, MIP-1β, and TARC) competed with LARC-SEAP for binding to GPR-CY4. By Northern blot analysis, GPR-CY4 mRNA was expressed mainly in speen, lymph nodes, Appendix, and fetal liver among various human tissues. Among various leukocyte subsets, GPR-CY4 mRNA was detected in lymphocytes (CD4 + and CD8 + T cells and B cells) but not in natural killer cells, monocytes, or granulocytes. Expression of GPR-CY4 mRNA in CD4 + and CD8 + T cells was strongly up-regulated by IL-2. Taken together, GPR-CY4 is the specific receptor for LARC expressed selectively on lymphocytes, and LARC is a unique functional ligand for GPR-CY4. We propose GPR-CY4 to be designated as CCR6.