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Gene Review

CCL3  -  chemokine (C-C motif) ligand 3

Homo sapiens

Synonyms: C-C motif chemokine 3, G0/G1 switch regulatory protein 19-1, G0S19-1, LD78ALPHA, MIP-1-alpha, ...


Human CCL3 was described as an inhibitor of bone marrow stem-cell proliferation by Lord and coworkers in 1976 [1]. It was identified at the nucleic acid level in 1985 as a 0.98 and 1. 12 kb mRNA doublet that showed rapid differential expression in human peripheral blood mononuclear cells cultured with the lectin, Concanavalin-A, and cycloheximide. The highly selective cDNA cloning procedure had been designed to identify members of a set of putative G0/G1 switch (G0S) regulatory genes, and the gene was named G0S19. Rapid induction was by either Concanavalin-A alone, or by cycloheximide alone [2]. Fuller characterization as part of a family of genes (G0S19-1, G0S19-2 , G0S19-3 and a strange oncogene-associated fragment) was reported in 1990 [3] , 1993 [4], and 1998 [5] .


Disease relevance of CCL3


Psychiatry related information on CCL3

  • Low, but detectable, levels of CSF MIP-1alpha were strongly associated with dementia, suggesting that higher levels may have neuroprotective effects [9].

High impact information on CCL3


Chemical compound and disease context of CCL3


Biological context of CCL3

  • First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03) [6].
  • Interestingly, FcepsilonRI engagement inhibited CCL3-mediated chemotaxis and membrane ruffling of RBL-CCR1 cells [17].
  • CP-481,715 retains activity in human whole blood, inhibiting CCL3-induced CD11b up-regulation and actin polymerization (IC50 = 165 and 57 nm, respectively) on monocytes [18].
  • Radiolabeled binding studies indicate that CP-481,715 binds to human CCR1 with a Kd of 9.2 nm and displaces 125I-labeled CCL3 from CCR1-transfected cells with an IC50 of 74 nm [18].
  • Our findings suggest that infants who display a deficient-production phenotype of CCL3 are at increased risk of acquiring HIV-1, indicating that this chemokine in particular plays an essential role in protective immunity [19].

Anatomical context of CCL3

  • Human memory CD4(+) T cells respond better to inflammatory CCLs/CC chemokines, CCL3 and CCL5, than naive CD4(+) T cells [20].
  • Activated lymphocytes synthesize and secrete substantial amounts of the beta-chemokines macrophage inflammatory protein (MIP)-1 alpha/CCL3 and MIP-1 beta/CCL4, both of which inhibit infection of cells with human immunodeficiency virus type 1 (HIV-1) [21].
  • CCL3 (MIP-1alpha), a prototype of CC chemokines, is a potent chemoattractant toward human neutrophils pre-treated with GM-CSF for 15 min [22].
  • It was observed that mitogen-induced production of CCL3 and CCL4 by cord-blood mononuclear cells was increased among infants born to HIV-positive compared with HIV-negative mothers, and that a deficiency in production of CCL3 was associated with increased susceptibility to intrapartum HIV-1 infection [19].
  • Differential pattern of CCR1 internalization in human eosinophils: prolonged internalization by CCL5 in contrast to CCL3 [23].

Associations of CCL3 with chemical compounds

  • Thirty-three point mutants of CCR1 were expressed transiently in L1.2 cells, and the cells were assessed for their capacity to migrate in response to CCL3 in the presence or absence of UCB 35625 [24].
  • The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451 [25].
  • MPTP treatment resulted in decreased CCL2 expression and increased CCL3 expression in the surviving dopaminergic neurons [26].
  • After 24 h, consistent upregulatory effects of all sensitizing compounds on transcript expression of CCL2, CCL3 and CCL4 were observed, whereas SDS (and BC) had no effect [27].
  • Both MSU and CPPD increased the secretion of IL-8 by neutrophils in a dose- and time-dependent manner, but had no effect on that of MIP-1 alpha [28].

Physical interactions of CCL3

  • The transfectants (YT4/293) showed high affinity binding for 125I-MCP3 in addition to specifically binding 125I-MIP1 alpha and 125I-Rantes [29].
  • These results suggest that MCP-1 and RANTES receptors are promiscuously coupled to multiple G proteins in IANK cell membranes and that this coupling is different from MIP-1 alpha receptors, which seem to be coupled to G(s), G(o), and G(z) but not to G(i) [30].
  • The present manuscript details the discovery and early fundamental structure-activity relationship studies involving compound 3, a novel hydroxyethylene peptide isostere derived molecule that provides micromolar inhibition of CCL3 binding to its receptor CCR1 [31].

Regulatory relationships of CCL3


Other interactions of CCL3


Analytical, diagnostic and therapeutic context of CCL3


  1. Inhibitor of stem cell proliferation in normal bone marrow. Lord, B.I., Mori, K.J., Wright, E.G., Lajtha, L.G. Br. J. Haematol. (1976) [Pubmed]
  2. cDNA cloning of mRNAS which increase rapidly in human lymphocytes cultured with concanavalin-A and cycloheximide. Forsdyke, D.R. Biochem. Biophys. Res. Commun. (1985) [Pubmed]
  3. Three human homologs of a murine gene encoding an inhibitor of stem cell proliferation. Blum, S., Forsdyke, R.E., Forsdyke, D.R. DNA. Cell. Biol. (1990) [Pubmed]
  4. The third human homolog of a murine gene encoding an inhibitor of stem cell proliferation is truncated and linked to a CpG island-containing upstream sequence. Russell, L., Forsdyke, D.R. DNA. Cell. Biol. (1993) [Pubmed]
  5. The normal copy of the G0S19-3-associated, CpG island-containing, upstream sequence is downstream of G0S19-2/MIP1alpha in association with a TRE17 oncogene. Heximer, S.P., Ernst, B.D., Russell, L., Forsdyke, D.R. DNA. Cell. Biol. (1998) [Pubmed]
  6. Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression. Modi, W.S., Lautenberger, J., An, P., Scott, K., Goedert, J.J., Kirk, G.D., Buchbinder, S., Phair, J., Donfield, S., O'Brien, S.J., Winkler, C. Am. J. Hum. Genet. (2006) [Pubmed]
  7. Role of chemokines in the biology of natural killer cells. Robertson, M.J. J. Leukoc. Biol. (2002) [Pubmed]
  8. Expression of chemokines in cerebrospinal fluid and serum of patients with chronic inflammatory demyelinating polyneuropathy. Mahad, D.J., Howell, S.J., Woodroofe, M.N. J. Neurol. Neurosurg. Psychiatr. (2002) [Pubmed]
  9. Cerebrospinal fluid beta chemokine concentrations in neurocognitively impaired individuals infected with human immunodeficiency virus type 1. Letendre, S.L., Lanier, E.R., McCutchan, J.A. J. Infect. Dis. (1999) [Pubmed]
  10. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Schall, T.J., Bacon, K., Toy, K.J., Goeddel, D.V. Nature (1990) [Pubmed]
  11. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Cocchi, F., DeVico, A.L., Garzino-Demo, A., Arya, S.K., Gallo, R.C., Lusso, P. Science (1995) [Pubmed]
  12. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. Daugherty, B.L., Siciliano, S.J., DeMartino, J.A., Malkowitz, L., Sirotina, A., Springer, M.S. J. Exp. Med. (1996) [Pubmed]
  13. Inhibition of macrophage inflammatory protein-1 alpha production by Epstein-Barr virus. Jabs, W.J., Wagner, H.J., Maurmann, S., Hennig, H., Kreft, B. Blood (2002) [Pubmed]
  14. Treatment of marrow stroma with interferon-alpha restores normal beta 1 integrin-dependent adhesion of chronic myelogenous leukemia hematopoietic progenitors. Role of MIP-1 alpha. Bhatia, R., McGlave, P.B., Verfaillie, C.M. J. Clin. Invest. (1995) [Pubmed]
  15. Directed selection of MIP-1 alpha neutralizing CCR5 antibodies from a phage display human antibody library. Osbourn, J.K., Earnshaw, J.C., Johnson, K.S., Parmentier, M., Timmermans, V., McCafferty, J. Nat. Biotechnol. (1998) [Pubmed]
  16. Lipopolysaccharide from an Escherichia coli htrB msbB mutant induces high levels of MIP-1 alpha and MIP-1 beta secretion without inducing TNF-alpha and IL-1 beta. Hone, D.M., Powell, J., Crowley, R.W., Maneval, D., Lewis, G.K. J. Hum. Virol. (1998) [Pubmed]
  17. Impact of engagement of FcepsilonRI and CC chemokine receptor 1 on mast cell activation and motility. Toda, M., Dawson, M., Nakamura, T., Munro, P.M., Richardson, R.M., Bailly, M., Ono, S.J. J. Biol. Chem. (2004) [Pubmed]
  18. CP-481,715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases. Gladue, R.P., Tylaska, L.A., Brissette, W.H., Lira, P.D., Kath, J.C., Poss, C.S., Brown, M.F., Paradis, T.J., Conklyn, M.J., Ogborne, K.T., McGlynn, M.A., Lillie, B.M., DiRico, A.P., Mairs, E.N., McElroy, E.B., Martin, W.H., Stock, I.A., Shepard, R.M., Showell, H.J., Neote, K. J. Biol. Chem. (2003) [Pubmed]
  19. Reduced ability of newborns to produce CCL3 is associated with increased susceptibility to perinatal human immunodeficiency virus 1 transmission. Meddows-Taylor, S., Donninger, S.L., Paximadis, M., Schramm, D.B., Anthony, F.S., Gray, G.E., Kuhn, L., Tiemessen, C.T. J. Gen. Virol. (2006) [Pubmed]
  20. An abortive ligand-induced activation of CCR1-mediated downstream signaling event and a deficiency of CCR5 expression are associated with the hyporesponsiveness of human naive CD4+ T cells to CCL3 and CCL5. Sato, K., Kawasaki, H., Morimoto, C., Yamashima, N., Matsuyama, T. J. Immunol. (2002) [Pubmed]
  21. Natural truncation of the chemokine MIP-1 beta /CCL4 affects receptor specificity but not anti-HIV-1 activity. Guan, E., Wang, J., Roderiquez, G., Norcross, M.A. J. Biol. Chem. (2002) [Pubmed]
  22. CCL3 (MIP-1alpha) induces in vitro migration of GM-CSF-primed human neutrophils via CCR5-dependent activation of ERK 1/2. Ottonello, L., Montecucco, F., Bertolotto, M., Arduino, N., Mancini, M., Corcione, A., Pistoia, V., Dallegri, F. Cell. Signal. (2005) [Pubmed]
  23. Differential pattern of CCR1 internalization in human eosinophils: prolonged internalization by CCL5 in contrast to CCL3. Elsner, J., Dulkys, Y., Gupta, S., Escher, S.E., Forssmann, W.G., Kapp, A., Forssmann, U. Allergy (2005) [Pubmed]
  24. Site-directed mutagenesis of CC chemokine receptor 1 reveals the mechanism of action of UCB 35625, a small molecule chemokine receptor antagonist. de Mendonça, F.L., da Fonseca, P.C., Phillips, R.M., Saldanha, J.W., Williams, T.J., Pease, J.E. J. Biol. Chem. (2005) [Pubmed]
  25. Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist. Princen, K., Hatse, S., Vermeire, K., Aquaro, S., De Clercq, E., Gerlach, L.O., Rosenkilde, M., Schwartz, T.W., Skerlj, R., Bridger, G., Schols, D. J. Virol. (2004) [Pubmed]
  26. Chemokines in the MPTP model of Parkinson's disease: Absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration. Kalkonde, Y.V., Morgan, W.W., Sigala, J., Maffi, S.K., Condello, C., Kuziel, W., Ahuja, S.S., Ahuja, S.K. Brain Res. (2007) [Pubmed]
  27. Cytokine transcript profiling in CD34+-progenitor derived dendritic cells exposed to contact allergens and irritants. Verheyen, G.R., Schoeters, E., Nuijten, J.M., Van Den Heuvel, R.L., Nelissen, I., Witters, H., Van Tendeloo, V.F., Berneman, Z.N., Schoeters, G.E. Toxicol. Lett. (2005) [Pubmed]
  28. Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: a possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. Hachicha, M., Naccache, P.H., McColl, S.R. J. Exp. Med. (1995) [Pubmed]
  29. Monocyte chemotactic protein-3 (MCP3) interacts with multiple leukocyte receptors. C-C CKR1, a receptor for macrophage inflammatory protein-1 alpha/Rantes, is also a functional receptor for MCP3. Ben-Baruch, A., Xu, L., Young, P.R., Bengali, K., Oppenheim, J.J., Wang, J.M. J. Biol. Chem. (1995) [Pubmed]
  30. Differential coupling of CC chemokine receptors to multiple heterotrimeric G proteins in human interleukin-2-activated natural killer cells. al-Aoukaty, A., Schall, T.J., Maghazachi, A.A. Blood (1996) [Pubmed]
  31. The discovery of structurally novel CCR1 antagonists derived from a hydroxyethylene peptide isostere template. Kath, J.C., DiRico, A.P., Gladue, R.P., Martin, W.H., McElroy, E.B., Stock, I.A., Tylaska, L.A., Zheng, D. Bioorg. Med. Chem. Lett. (2004) [Pubmed]
  32. Increase of CCR1 and CCR5 expression and enhanced functional response to MIP-1 alpha during differentiation of human monocytes to macrophages. Kaufmann, A., Salentin, R., Gemsa, D., Sprenger, H. J. Leukoc. Biol. (2001) [Pubmed]
  33. Production of chemokines, interleukin-8 and monocyte chemoattractant protein-1, during monocyte: endothelial cell interactions. Lukacs, N.W., Strieter, R.M., Elner, V., Evanoff, H.L., Burdick, M.D., Kunkel, S.L. Blood (1995) [Pubmed]
  34. Effect of T helper 1 (Th1)/Th2 cytokine on chemokine-induced dendritic cell functions. Clingan, J.M., Yanagawa, Y., Iwabuchi, K., Onoé, K. Cell. Immunol. (2006) [Pubmed]
  35. Cloning and characterization of exodus, a novel beta-chemokine. Hromas, R., Gray, P.W., Chantry, D., Godiska, R., Krathwohl, M., Fife, K., Bell, G.I., Takeda, J., Aronica, S., Gordon, M., Cooper, S., Broxmeyer, H.E., Klemsz, M.J. Blood (1997) [Pubmed]
  36. Interleukin 13 inhibits macrophage inflammatory protein-1 alpha production from human alveolar macrophages and monocytes. Berkman, N., John, M., Roesems, G., Jose, P., Barnes, P.J., Chung, K.F. Am. J. Respir. Cell Mol. Biol. (1996) [Pubmed]
  37. RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. Rot, A., Krieger, M., Brunner, T., Bischoff, S.C., Schall, T.J., Dahinden, C.A. J. Exp. Med. (1992) [Pubmed]
  38. Formation of eosinophilic and monocytic intradermal inflammatory sites in the dog by injection of human RANTES but not human monocyte chemoattractant protein 1, human macrophage inflammatory protein 1 alpha, or human interleukin 8. Meurer, R., Van Riper, G., Feeney, W., Cunningham, P., Hora, D., Springer, M.S., MacIntyre, D.E., Rosen, H. J. Exp. Med. (1993) [Pubmed]
  39. Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway. del Pozo, M.A., Sánchez-Mateos, P., Nieto, M., Sánchez-Madrid, F. J. Cell Biol. (1995) [Pubmed]
  40. Identification and characterization of U83A viral chemokine, a broad and potent beta-chemokine agonist for human CCRs with unique selectivity and inhibition by spliced isoform. Dewin, D.R., Catusse, J., Gompels, U.A. J. Immunol. (2006) [Pubmed]
  41. CCR5 expression and CC chemokine levels in idiopathic pulmonary fibrosis. Capelli, A., Di Stefano, A., Gnemmi, I., Donner, C.F. Eur. Respir. J. (2005) [Pubmed]
  42. Macrophage inflammatory protein 1 alpha expression by synovial fluid neutrophils in rheumatoid arthritis. Hatano, Y., Kasama, T., Iwabuchi, H., Hanaoka, R., Takeuchi, H.T., Jing, L., Mori, Y., Kobayashi, K., Negishi, M., Ide, H., Adachi, M. Ann. Rheum. Dis. (1999) [Pubmed]
  43. Differential response of CD34+ cells isolated from cord blood and bone marrow to MIP-1 alpha and the expression of MIP-1 alpha receptors on these immature cells. de Wynter, E.A., Durig, J., Cross, M.A., Heyworth, C.M., Testa, N.G. Stem Cells (1998) [Pubmed]
  44. Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes. Lee, Y.H., Nair, S., Rousseau, E., Allison, D.B., Page, G.P., Tataranni, P.A., Bogardus, C., Permana, P.A. Diabetologia (2005) [Pubmed]
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