Alternative titles; symbols
HGNC Approved Gene Symbol: CCL3
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:36,088,256-36,090,143 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | {HIV infection, resistance to} | 609423 | 2 |
Macrophage inflammatory protein-1 is a so-called monokine that is involved in the acute inflammatory state in the recruitment and activation of polymorphonuclear leukocytes (Wolpe et al., 1988). Sherry et al. (1988) demonstrated 2 protein components of MIP1, called by them alpha and beta.
According to the review of Wolpe and Cerami (1989), cDNAs for MIP1A (MIP-1-alpha) and MIP1B (MIP-1-beta; 182284) are 57% identical and the predicted peptide sequences are 60% identical over their entire length. The cDNA for MIP1A predicts a mature peptide of 69 amino acids with a molecular mass of 7,889 daltons. The cDNA for MIP1B predicts a mature peptide of 69 amino acids with a molecular mass of 7,832 daltons; the presence of a potential N-glycosylation site (asn-pro-ser) at position 53 may account for the larger apparent size of the MIP1B protein by SDS-PAGE. MIP1A is also known as LD78.
Mitogenic stimulation of resting T cells results in the de novo transcription of a large number of genes including those encoding regulatory molecules such as lymphokines. Irving et al. (1990) determined the genomic organization of the genes for 2 induced lymphokines that appear to be the human homologs of the murine macrophage inflammatory proteins, Mip-1-alpha and -beta, which they called 464.1 and 744.1, respectively. The 2 genes shared 55% amino acid homology and demonstrated parallel regulation of induced expression in T cells. Irving et al. (1990) found, furthermore, that the genes are closely linked in the human genome, separated by 14 kb, and are organized in a head-to-head fashion. Close linkage was also indicated by the finding of linkage disequilibrium in population studies. Irving et al. (1990) assigned Mip-1-alpha and -beta to 17q11-q21 by study of somatic cell hybrids and by in situ hybridization.
Hirashima et al. (1992) mapped the 3 LD78 genes, including LD78-alpha, to chromosome 17q21.1-q21.3 by in situ hybridization and somatic cell hybrid analysis.
Modi et al. (2006) stated that CCL18 (603757), CCL3, and CCL4 (182284) lie in a 47-kb interval on 17q12.
By analysis of somatic cell hybrids and recombinant inbred strains, Wilson et al. (1990) mapped the mouse Mip1a and Mip1b genes to a cluster on chromosome 11.
The human gene was identified as an early G0/G1 switch gene in cultured blood mononuclear cells and named G0S19 (Blum et al., 1990). Blum et al. (1990) and Nakao et al. (1990) obtained evidence for the existence of at least 3 different LD78-like genes in the human genome.
Cocchi et al. (1995) identified RANTES (187011), MIP-1-alpha, and MIP-1-beta as the major HIV-suppressive factors produced by CD8-positive T cells.
Using microarray analysis of gene expression signatures, Lossos et al. (2004) studied prediction of prognosis in diffuse large B-cell lymphoma. In a univariate analysis, genes were ranked on the basis of their ability to predict survival; the strongest predictors of longer overall survival were LMO2 (180385), BCL6 (109565), and FN1 (135600), and the strongest predictors of shorter overall survival were CCND2 (123833), SCYA3, and BCL2 (151430). Lossos et al. (2004) developed a multivariate model that was based on the expression of these 6 genes, and validated the model in 2 independent microarray data sets. The model was independent of the International Prognostic Index and added to its predictive power.
In diseased mouse and human arteries, Zhao et al. (2004) demonstrated that 5-lipoxygenase (5-LO; 152390)-positive macrophages localize to areas of neoangiogenesis and that these cells constitute a main component of aortic aneurysms induced by an atherogenic diet containing cholate in Apoe (107741) -/- mice. 5-LO deficiency markedly attenuated the formation of these aneurysms and was associated with reduced matrix metalloproteinase-2 (MMP2; 120360) activity and diminished plasma CCL3, but only minimally affected the formation of lipid-rich lesions. The leukotriene LTD4 strongly stimulated expression of CCL3 in macrophages and CXCL2 (139110) in endothelial cells. Zhao et al. (2004) concluded that the 5-LO pathway is linked to hyperlipidemia-dependent inflammation of the arterial wall and to the pathogenesis of aortic aneurysms through a potential chemokine intermediary route.
Mueller and Strange (2004) presented evidence that activation of CCR5 (601373) by CCL3 directly and independently activates a G-protein signaling pathway through GNAI2 (139360) and a tyrosine phosphorylation signaling pathway through JAK2 (147796).
Schistosoma species (see 181460) are helminth parasites that are adept at manipulating the host immune system to allow tolerance of chronic worm infections without overt morbidity. This modulation of immunity by schistosomes prevents a range of immune-mediated diseases, including allergies and autoimmunity. Smith et al. (2005) identified a molecule produced by Schistosoma eggs, termed S. mansoni chemokine-binding protein (smCKBP), that bound several chemokines, including CCL3. SmCKBP blocked interaction of these chemokines with their receptors and thereby inhibited induction of inflammation. Smith et al. (2005) proposed that since smCKBP is unrelated to host proteins, it may have potential as an antiinflammatory agent.
Dong et al. (2016) reported that Ptpn11 (176876) activating mutations in the mouse bone marrow microenvironment promoted the development and progression of myeloproliferative neoplasm (MPN) through profound detrimental effects on hematopoietic stem cells. Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, caused excessive production of the CC chemokine CCL3, which recruited monocytes to the area in which hematopoietic stem cells also resided. Consequently, hematopoietic stem cells were hyperactivated by interleukin-1-beta (IL1B; 147720) and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reversed MPN development induced by the Ptpn11-mutated bone marrow microenvironment. Dong et al. (2016) concluded that their study revealed the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukemogenesis and identified CCL3 as a potential therapeutic target for controlling leukemic progression in Noonan syndrome (163950) and for improving stem cell transplantation therapy in Noonan syndrome-associated leukemias.
CCL3, CCL4 (182284), and CCL18 (603757), which are located within 40 kb of each other, encode potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mass cells, CD4+ T cells, and CD8+ T cells. CCL3 and CCL4 are natural ligands for the HIV-1 coreceptor CCR5 and also activate and enhance the cytotoxicity of natural killer cells. Modi et al. (2006) genotyped genomic DNA from more than 3,000 participants enrolled in 5 United States-based natural-history cohorts with AIDS for 21 SNPs in a 47-kb interval on 17q12 containing these 3 genes. Two significant associations were reported that replicated an earlier study. First, among the African American members of the cohort of injection drug users, frequencies of 3 correlated SNPs in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconverters (P = 0.02-0.03). Second, 7 highly correlated SNPs spanning 36 kb and containing all 3 genes were significantly associated with more-rapid disease progression among American Europeans. These results reiterated the importance of chemokine gene variation in HIV-1/AIDS pathogenesis and emphasized that localized linkage disequilibrium makes the identification of causal mutations difficult.
Cook et al. (1995) examined the biologic role of MIP-1-alpha by generating mice homozygous for a knockout of the gene. They found that homozygotes were resistant to Coxsackievirus-induced myocarditis seen in infected wildtype mice. Influence of virus-infected homozygous MIP-1-alpha mice had reduced pneumonitis and delayed clearance of the virus compared with infected wildtype mice. The homozygous deficient mice had no overt hematopoietic abnormalities. The results demonstrated that MIP-1-alpha is an important mediator of virus-induced inflammation in vivo.
Miyazaki et al. (2005) showed that IgE-mediated immediate hypersensitivity reactions in the conjunctiva require multiple signals. They found that immediate hypersensitivity and mast cell degranulation were inhibited in mice lacking Mip1a, which had normal numbers of tissue mast cells and no decrease in the levels of allergen-specific IgE, and in mice treated with anti-Mip1a. Miyazaki et al. (2005) concluded that MIP1A is an important second signal for mast cell degranulation in the conjunctiva and for acute-phase disease, possibly through interaction with CCR1 (601159), its chemokine receptor.
Blum, S., Forsdyke, R. E., Forsdyke, D. R. Three human homologs of a murine gene encoding an inhibitor of stem cell proliferation. DNA Cell Biol. 9: 589-602, 1990. [PubMed: 2271120] [Full Text: https://doi.org/10.1089/dna.1990.9.589]
Cocchi, F., DeVico, A. L., Garzino-Demo, A., Arya, S. K., Gallo, R. C., Lusso, P. Identification of RANTES, MIP-1-alpha, and MIP-1-beta as the major HIV-suppressive factors produced by CD8(+) T cells. Science 270: 1811-1815, 1995. [PubMed: 8525373] [Full Text: https://doi.org/10.1126/science.270.5243.1811]
Cook, D. N., Beck, M. A., Coffman, T. M., Kirby, S. L., Sheridan, J. F., Pragnell, I. B., Smithies, O. Requirement of MIP-1-alpha for an inflammatory response to viral infection. Science 269: 1583-1585, 1995. [PubMed: 7667639] [Full Text: https://doi.org/10.1126/science.7667639]
Dong, L., Yu, W.-M., Zheng, H., Loh, M. L., Bunting, S. T., Pauly, M., Huang, G., Zhou, M., Broxmeyer, H. E., Scadden, D. T., Qu, C.-K. Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature 539: 304-308, 2016. [PubMed: 27783593] [Full Text: https://doi.org/10.1038/nature20131]
Hirashima, M., Ono, T., Nakao, M., Nishi, H., Kimura, A., Nomiyama, H., Hamada, F., Yoshida, M. C., Shimada, K. Nucleotide sequence of the third cytokine LD78 gene and mapping of all three LD78 gene loci to human chromosome 17. DNA Seq. 3: 203-212, 1992. [PubMed: 1296815] [Full Text: https://doi.org/10.3109/10425179209034019]
Irving, S. G., Zipfel, P. F., Balke, J., McBride, O. W., Morton, C. C., Burd, P. R., Siebenlist, U., Kelly, K. Two inflammatory mediator cytokine genes are closely linked and variably amplified on chromosome 17q. Nucleic Acids Res. 18: 3261-3270, 1990. [PubMed: 1972563] [Full Text: https://doi.org/10.1093/nar/18.11.3261]
Lossos, I. S., Czerwinski, D. K., Alizadeh, A. A., Wechser, M. A., Tibshirani, R., Botstein, D., Levy, R. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. New Eng. J. Med. 350: 1828-1837, 2004. [PubMed: 15115829] [Full Text: https://doi.org/10.1056/NEJMoa032520]
Miyazaki, D., Nakamura, T., Toda, M., Cheung-Chau, K.-W., Richardson, R. M., Ono, S. J. Macrophage inflammatory protein-1-alpha as a costimulatory signal for mast cell-mediated immediate hypersensitivity reactions. J. Clin. Invest. 115: 434-442, 2005. [PubMed: 15650768] [Full Text: https://doi.org/10.1172/JCI18452]
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. Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV type 1 transmission and AIDS disease progression. Am. J. Hum. Genet. 79: 120-128, 2006. [PubMed: 16773571] [Full Text: https://doi.org/10.1086/505331]
Mueller, A., Strange, P. G. CCL3, acting via the chemokine receptor CCR5, leads to independent activation of Janus kinase 2 (JAK2) and G(i) proteins. FEBS Lett. 570: 126-132, 2004. [PubMed: 15251452] [Full Text: https://doi.org/10.1016/j.febslet.2004.04.100]
Nakao, M., Nomiyama, H., Shimada, K. Structures of human genes coding for cytokine LD78 and their expression. Molec. Cell. Biol. 10: 3646-3658, 1990. [PubMed: 1694014] [Full Text: https://doi.org/10.1128/mcb.10.7.3646-3658.1990]
Sherry, B., Tekamp-Olson, P., Gallegos, C., Bauer, D., Davatelis, G., Wolpe, S. D., Masiarz, F., Coit, D., Cerami, A. Resolution of the two components of macrophage inflammatory protein 1, and cloning and characterization of one of those components, macrophage inflammatory protein 1-beta. J. Exp. Med. 168: 2251-2259, 1988. [PubMed: 3058856] [Full Text: https://doi.org/10.1084/jem.168.6.2251]
Smith, P., Fallon, R. E., Mangan, N. E., Walsh, C. M., Saraiva, M., Sayers, J. R., McKenzie, A. N. J., Alcami, A., Fallon, P. G. Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity. J. Exp. Med. 202: 1319-1325, 2005. [PubMed: 16301741] [Full Text: https://doi.org/10.1084/jem.20050955]
Wilson, S. D., Billings, P. R., D'Eustachio, P., Fournier, R. E. K., Geissler, E., Lalley, P. A., Burd, P. R., Housman, D. E., Taylor, B. A., Dorf, M. E. Clustering of cytokine genes on mouse chromosome 11. J. Exp. Med. 171: 1301-1314, 1990. [PubMed: 1969921] [Full Text: https://doi.org/10.1084/jem.171.4.1301]
Wolpe, S. D., Cerami, A. Macrophage inflammatory proteins 1 and 2: members of a novel superfamily of cytokines. FASEB J. 3: 2565-2573, 1989. [PubMed: 2687068] [Full Text: https://doi.org/10.1096/fasebj.3.14.2687068]
Wolpe, S. D., Davatelis, G., Sherry, B., Beutler, B., Hesse, D. G., Nguyen, H. T., Moldawer, L. L., Nathan, C. F., Lowry, S. F., Cerami, A. Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties. J. Exp. Med. 167: 570-581, 1988. [PubMed: 3279154] [Full Text: https://doi.org/10.1084/jem.167.2.570]
Zhao, L., Moos, M. P. W., Grabner, R., Pedrono, F., Fan, J., Kaiser, B., John, N., Schmidt, S., Spanbroek, R., Lotzer, K., Huang, L., Cui, J., Rader, D. J., Evans, J. F., Habenicht, A. J. R., Funk, C. D. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nature Med. 10: 966-973, 2004. [PubMed: 15322539] [Full Text: https://doi.org/10.1038/nm1099]