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Gene Review

CCR4  -  chemokine (C-C motif) receptor 4

Homo sapiens

Synonyms: C-C CKR-4, C-C chemokine receptor type 4, CC-CKR-4, CCR-4, CD194, ...
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Disease relevance of CCR4


High impact information on CCR4


Chemical compound and disease context of CCR4

  • Potential role of the chemokine receptors CXCR3, CCR4, and the integrin alphaEbeta7 in the pathogenesis of psoriasis vulgaris [8].
  • RATIONALE: The chemokine receptors CXCR3 and CCR4 have recently been described as playing a pivotal role in the mouse model of bleomycin-induced fibrosis [9].
  • CONCLUSION: The study describes a delayed hypersensitivity to suxamethonium, driven by an oligoclonal T helper cell 1-skewed CD4+ memory T cell population, expressing the skin homing receptors CLA and CCR4 [10].
  • DESIGN AND METHODS: Ten patients 45 years of age or older with hematologic malignancies received a CD34+-PBSCT and cyclosporin A (CyA) to prevent acute GVHD, followed by a planned delayed donor TCAB of 107 T-cells/kg to restore the graft-versus-tumor effect [11].
  • INTERPRETATION AND CONCLUSIONS: CD34+/ASCT using BCNU, Cy and ATG as conditioning regimen has an acceptable toxicity and clearly reduces the progression of MS [12].

Biological context of CCR4

  • Activation of phosphoinositide 3-kinases by the CCR4 ligand macrophage-derived chemokine is a dispensable signal for T lymphocyte chemotaxis [13].
  • These findings suggest that the different regulatory pathways in which hCAF1 is involved, notably transcription regulation and mRNA turnover, may occur through distinct CCR4 complexes in the course of cell-cycle progression [14].
  • Other chemokines acting on CCR2, CCR4 and CCR5 failed to protect against apoptosis and to induce BW5147 chemotaxis, suggesting that these receptors were not functionally expressed [15].
  • The fifth gene (CMKBR4, encoding the CC-CKR4 receptor) was located more distally (3p24) on the same chromosome, between the FB18G7 and the D3S1768 markers [16].
  • These findings suggest that CCR4+ T cells in the JRA joint may function early in disease in an anti-inflammatory capacity through the production of type 2 cytokines and may play a role in determining disease phenotype [17].

Anatomical context of CCR4


Associations of CCR4 with chemical compounds

  • The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics [18].
  • Inhibition of Ins(1,4,5)P3 receptor-mediated calcium release from intracellular stores had no effect on chemotactic responses to CCR4 ligands [20].
  • AMD3100 did not, on its own, induce a calcium flux in the CCRF-CEM cells, which express multiple GPCRs including CXCR4, CCR4 and CCR7 [21].
  • In the intestinal samples, CCR5 was detected in all the cases with BD, whereas Th2-related CCR3 and CCR4 were detected randomly, mainly in the cases with inactive BD and those receiving large amounts of prednisolone, indicating the Th1-dominant immune responses in the intestinal lesions [22].
  • These results suggest that recruitment of IL-4-producing CCR4(+) CD4(+) T cells by granuloma-derived TARC into the liver parenchyma may be a key cause of massive liver injury after systemic LPS administration [23].

Physical interactions of CCR4

  • BTG2 antiproliferative protein interacts with the human CCR4 complex existing in vivo in three cell-cycle-regulated forms [14].
  • TARC interacts primarily with the CCR4 receptor and to a lesser extent with the CCR8 receptor [24].
  • The chemokine receptor CCR4 binds MDC with high affinity and also responds by calcium flux and chemotaxis [25].

Regulatory relationships of CCR4


Other interactions of CCR4

  • In contrast, CCR3 and CCR4 were found on Th2s [31].
  • There is also evidence for expression of chemokine receptors CCR4 and CXCR4 in platelets [19].
  • K562 cells stably expressing CCR4 also responded to TARC in a calcium mobilization assay [27].
  • Also, CCR4 is internalized between 5 and 45 min but reappears in the membranes after 60 min of stimulation with MDC [32].
  • Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions [33].

Analytical, diagnostic and therapeutic context of CCR4


  1. Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Yoshie, O., Fujisawa, R., Nakayama, T., Harasawa, H., Tago, H., Izawa, D., Hieshima, K., Tatsumi, Y., Matsushima, K., Hasegawa, H., Kanamaru, A., Kamihira, S., Yamada, Y. Blood (2002) [Pubmed]
  2. Expression and function of chemokine receptors on human thymocytes: implications for infection by human immunodeficiency virus type 1. Taylor, J.R., Kimbrell, K.C., Scoggins, R., Delaney, M., Wu, L., Camerini, D. J. Virol. (2001) [Pubmed]
  3. Chemokine receptor expression on neoplastic and reactive T cells in the skin at different stages of mycosis fungoides. Kallinich, T., Muche, J.M., Qin, S., Sterry, W., Audring, H., Kroczek, R.A. J. Invest. Dermatol. (2003) [Pubmed]
  4. Increased CCR4 expression in cutaneous T cell lymphoma. Ferenczi, K., Fuhlbrigge, R.C., Pinkus, J., Pinkus, G.S., Kupper, T.S. J. Invest. Dermatol. (2002) [Pubmed]
  5. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Campbell, J.J., Haraldsen, G., Pan, J., Rottman, J., Qin, S., Ponath, P., Andrew, D.P., Warnke, R., Ruffing, N., Kassam, N., Wu, L., Butcher, E.C. Nature (1999) [Pubmed]
  6. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. Iellem, A., Mariani, M., Lang, R., Recalde, H., Panina-Bordignon, P., Sinigaglia, F., D'Ambrosio, D. J. Exp. Med. (2001) [Pubmed]
  7. CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo. Lloyd, C.M., Delaney, T., Nguyen, T., Tian, J., Martinez-A, C., Coyle, A.J., Gutierrez-Ramos, J.C. J. Exp. Med. (2000) [Pubmed]
  8. Potential role of the chemokine receptors CXCR3, CCR4, and the integrin alphaEbeta7 in the pathogenesis of psoriasis vulgaris. Rottman, J.B., Smith, T.L., Ganley, K.G., Kikuchi, T., Krueger, J.G. Lab. Invest. (2001) [Pubmed]
  9. Role of the chemokine receptors CXCR3 and CCR4 in human pulmonary fibrosis. Pignatti, P., Brunetti, G., Moretto, D., Yacoub, M.R., Fiori, M., Balbi, B., Balestrino, A., Cervio, G., Nava, S., Moscato, G. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  10. Delayed allergic reaction to suxamethonium driven by oligoclonal Th1-skewed CD4+CCR4+IFN-gamma+ memory T cells. Scala, E., Guerra, E.C., Giani, M., Pirrotta, L., Locanto, M., Mondino, C., Mari, A. Int. Arch. Allergy Immunol. (2006) [Pubmed]
  11. Allogeneic peripheral blood stem cell transplantation with CD34+-cell selection and delayed T-cell add-back in adults. Results of a single center pilot study. Martino, R., Martín-Henao, G., Sureda, A., Altés, A., Canals, C., Brunet, S., Sierra, J. Haematologica (2000) [Pubmed]
  12. CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of follow-up in 15 patients. Carreras, E., Saiz, A., Marín, P., Martínez, C., Rovira, M., Villamor, N., Aymerich, M., Lozano, M., Fernández-Avilés, F., Urbano-Izpizua, A., Montserrat, E., Graus, F. Haematologica (2003) [Pubmed]
  13. Activation of phosphoinositide 3-kinases by the CCR4 ligand macrophage-derived chemokine is a dispensable signal for T lymphocyte chemotaxis. Cronshaw, D.G., Owen, C., Brown, Z., Ward, S.G. J. Immunol. (2004) [Pubmed]
  14. BTG2 antiproliferative protein interacts with the human CCR4 complex existing in vivo in three cell-cycle-regulated forms. Morel, A.P., Sentis, S., Bianchin, C., Le Romancer, M., Jonard, L., Rostan, M.C., Rimokh, R., Corbo, L. J. Cell. Sci. (2003) [Pubmed]
  15. CCR8-dependent activation of the RAS/MAPK pathway mediates anti-apoptotic activity of I-309/ CCL1 and vMIP-I. Louahed, J., Struyf, S., Demoulin, J.B., Parmentier, M., Van Snick, J., Van Damme, J., Renauld, J.C. Eur. J. Immunol. (2003) [Pubmed]
  16. The genes encoding the human CC-chemokine receptors CC-CKR1 to CC-CKR5 (CMKBR1-CMKBR5) are clustered in the p21.3-p24 region of chromosome 3. Samson, M., Soularue, P., Vassart, G., Parmentier, M. Genomics (1996) [Pubmed]
  17. Chemokine receptor CCR4 on CD4+ T cells in juvenile rheumatoid arthritis synovial fluid defines a subset of cells with increased IL-4:IFN-gamma mRNA ratios. Thompson, S.D., Luyrink, L.K., Graham, T.B., Tsoras, M., Ryan, M., Passo, M.H., Glass, D.N. J. Immunol. (2001) [Pubmed]
  18. The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics. Panina-Bordignon, P., Papi, A., Mariani, M., Di Lucia, P., Casoni, G., Bellettato, C., Buonsanti, C., Miotto, D., Mapp, C., Villa, A., Arrigoni, G., Fabbri, L.M., Sinigaglia, F. J. Clin. Invest. (2001) [Pubmed]
  19. Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Clemetson, K.J., Clemetson, J.M., Proudfoot, A.E., Power, C.A., Baggiolini, M., Wells, T.N. Blood (2000) [Pubmed]
  20. Evidence that phospholipase-C-dependent, calcium-independent mechanisms are required for directional migration of T-lymphocytes in response to the CCR4 ligands CCL17 and CCL22. Cronshaw, D.G., Kouroumalis, A., Parry, R., Webb, A., Brown, Z., Ward, S.G. J. Leukoc. Biol. (2006) [Pubmed]
  21. Characterization of the molecular pharmacology of AMD3100: a specific antagonist of the G-protein coupled chemokine receptor, CXCR4. Fricker, S.P., Anastassov, V., Cox, J., Darkes, M.C., Grujic, O., Idzan, S.R., Labrecque, J., Lau, G., Mosi, R.M., Nelson, K.L., Qin, L., Santucci, Z., Wong, R.S. Biochem. Pharmacol. (2006) [Pubmed]
  22. Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet's disease. Imamura, Y., Kurokawa, M.S., Yoshikawa, H., Nara, K., Takada, E., Masuda, C., Tsukikawa, S., Ozaki, S., Matsuda, T., Suzuki, N. Clin. Exp. Immunol. (2005) [Pubmed]
  23. Pivotal role of TARC, a CC chemokine, in bacteria-induced fulminant hepatic failure in mice. Yoneyama, H., Harada, A., Imai, T., Baba, M., Yoshie, O., Zhang, Y., Higashi, H., Murai, M., Asakura, H., Matsushima, K. J. Clin. Invest. (1998) [Pubmed]
  24. Structures of thymus and activation-regulated chemokine (TARC). Asojo, O.A., Boulègue, C., Hoover, D.M., Lu, W., Lubkowski, J. Acta Crystallogr. D Biol. Crystallogr. (2003) [Pubmed]
  25. Profile of human macrophage transcripts: insights into macrophage biology and identification of novel chemokines. Chantry, D., DeMaggio, A.J., Brammer, H., Raport, C.J., Wood, C.L., Schweickart, V.L., Epp, A., Smith, A., Stine, J.T., Walton, K., Tjoelker, L., Godiska, R., Gray, P.W. J. Leukoc. Biol. (1998) [Pubmed]
  26. CCR4 ligands are up-regulated in the airways of atopic asthmatics after segmental allergen challenge. Pilette, C., Francis, J.N., Till, S.J., Durham, S.R. Eur. Respir. J. (2004) [Pubmed]
  27. The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4. Imai, T., Baba, M., Nishimura, M., Kakizaki, M., Takagi, S., Yoshie, O. J. Biol. Chem. (1997) [Pubmed]
  28. CC chemokine receptor 4 ligand production by bronchoalveolar lavage fluid cells in cigarette-smoke-associated acute eosinophilic pneumonia. Nureki, S., Miyazaki, E., Ando, M., Kumamoto, T., Tsuda, T. Clin. Immunol. (2005) [Pubmed]
  29. Roxithromycin downmodulates Th2 chemokine production by keratinocytes and chemokine receptor expression on Th2 cells: its dual inhibitory effects on the ligands and the receptors. Kobayashi, M., Shimauchi, T., Hino, R., Tokura, Y. Cell. Immunol. (2004) [Pubmed]
  30. Clonal Th2 cells associated with chronic hypereosinophilia: TARC-induced CCR4 down-regulation in vivo. de Lavareille, A., Roufosse, F., Schandené, L., Stordeur, P., Cogan, E., Goldman, M. Eur. J. Immunol. (2001) [Pubmed]
  31. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. Sallusto, F., Lenig, D., Mackay, C.R., Lanzavecchia, A. J. Exp. Med. (1998) [Pubmed]
  32. Human NK cells express CC chemokine receptors 4 and 8 and respond to thymus and activation-regulated chemokine, macrophage-derived chemokine, and I-309. Inngjerdingen, M., Damaj, B., Maghazachi, A.A. J. Immunol. (2000) [Pubmed]
  33. Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions. Bochner, B.S., Hudson, S.A., Xiao, H.Q., Liu, M.C. J. Allergy Clin. Immunol. (2003) [Pubmed]
  34. Macrophage-derived chemokine induces human eosinophil chemotaxis in a CC chemokine receptor 3- and CC chemokine receptor 4-independent manner. Bochner, B.S., Bickel, C.A., Taylor, M.L., MacGlashan, D.W., Gray, P.W., Raport, C.J., Godiska, R. J. Allergy Clin. Immunol. (1999) [Pubmed]
  35. Selective infiltration of CCR5(+)CXCR3(+) T lymphocytes in human colorectal carcinoma. Musha, H., Ohtani, H., Mizoi, T., Kinouchi, M., Nakayama, T., Shiiba, K., Miyagawa, K., Nagura, H., Yoshie, O., Sasaki, I. Int. J. Cancer (2005) [Pubmed]
  36. Multiple determinants are involved in HIV coreceptor use as demonstrated by CCR4/CCL22 interaction in peripheral blood mononuclear cells (PBMCs). Agrawal, L., Vanhorn-Ali, Z., Alkhatib, G. J. Leukoc. Biol. (2002) [Pubmed]
  37. Accumulation of CCR4-expressing CD4+ T cells and high concentration of its ligands (TARC and MDC) in bronchoalveolar lavage fluid of patients with eosinophilic pneumonia. Katoh, S., Fukushima, K., Matsumoto, N., Matsumoto, K., Abe, K., Onai, N., Matsushima, K., Matsukura, S. Allergy (2003) [Pubmed]
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