Alternative titles; symbols
HGNC Approved Gene Symbol: CCL4
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:36,103,827-36,105,614 (from NCBI)
By differential hybridization screening of an activated T-cell library, Lipes et al. (1988) identified an immune activation gene, denoted ACT2. The gene was induced rapidly after T-cell activation with phytohemagglutinin, B-cell activation with Staphylococcus aureus, and monocyte activation with lipopolysaccharide. Lipes et al. (1988) isolated a cDNA containing the full-length coding region. The deduced amino acid sequence predicted an open reading frame of 92 amino acids, including a very hydrophobic N terminus, which was predicted to be a signal peptide. Using a baculovirus expression system, they showed that the gene encodes a secreted product. Therefore, it seemed likely that ACT2 was a cytokine.
Irving et al. (1990) identified human homologs of MIP-1-alpha (182283) and MIP-1-beta, designating them 464.1 and 744.1, respectively. They stated that the 2 genes demonstrate parallel regulation following activation of T cells with various mitogens and encode proteins that share 55% sequence similarity. The 464.1 and 744.1 genes are separated by 14 kb in the genome, and are arranged in a head-to-head fashion. Each of the genes is present as an additional copy, which they referred to as 464.2 (SCYA3L1; 601395) and 744.2 (CCL4L; 603782), respectively.
MIP1B is an 8-kD acidic protein that is upregulated upon stimulation in monocytes, T cells, and other lymphocytes. It belongs to the CC chemokine subfamily and directs the migration of specific subsets of leukocytes. Modi et al. (2001) noted that there had been confusion regarding the exact number of genes encoding MIP1B and related proteins ever since the first MIP1B molecular clone was isolated. They demonstrated that MIP1B is encoded by 2 paralogous genes, ACT2 (CCL4) and LAG1 (CCL4L), that are closely situated on the long arm of chromosome 17. The proteins share a common length and are identical at 89 of 92 amino acids. The first 2 amino acid differences occur in the signal peptide, while the third is in the mature protein. Within the transcribed region, the genes differ at 25 of 662 nucleotides.
Using RT-PCR analysis, Lu et al. (2004) showed that ACT2 and LAG1 are distinct genes and that monocytes predominantly express ACT2, whereas peripheral B lymphocytes express a mixture of ACT2 and LAG1. Lu et al. (2004) also identified B-cell lines that express predominantly LAG1. They concluded that monocytes and B cells use different mechanisms to regulate expression of the 2 genes. Lu et al. (2004) suggested that the most effective anti-HIV drugs would be those that increase expression of whichever CCL4 protein, i.e., ACT2 or LAG1, has the highest affinity for CCR5 (601373).
Colobran et al. (2005) showed that both CCL4 and CCL4L generate splice variants lacking exon 2.
Cocchi et al. (1995) identified RANTES (187011), MIP-1-alpha (182283), and MIP-1-beta as the major HIV-suppressive factors produced by CD8+ T cells.
Kamin-Lewis et al. (2001) demonstrated that it is predominantly perforin (170280)-low memory CD8+ T cells that normally synthesize MIP-1-beta. This beta-chemokine is clearly synthesized by a major population of CD8+ T cells that has a phenotype that is not consistent with cytotoxic T-lymphocyte effector function. The authors suggested that nonlytic CD8+ T-cell subsets should be examined as correlates of protective immunity against HIV-1.
Napolitano et al. (1991) sequenced the exons and exon/intron splice junctions as well as the sequences upstream of exon 1 of the ACT2 gene. A classic TATA box was located immediately upstream of the transcription initiation site. The upstream sequences possess promoter activity.
By analysis of somatic cell hybrids and by in situ hybridization, Modi et al. (1991) assigned the SCYA4 gene to a slightly more distal location than had Irving et al. (1990): 17q21-q23 rather than 17q11-q21. Tasaki et al. (1999) reported the arrangement of AT744.1 with respect to the other genes in the CC chemokine gene cluster at 17q11.2. By genomic sequence analysis, Modi et al. (2001) determined that the ACT2 and LAG1 genes are located about 651 kb apart on chromosome 17.
Modi et al. (2006) stated that CCL18 (603757), CCL3 (182283), and CCL4 lie in a 47-kb interval on 17q12.
Modi et al. (2001) stated that ACT2 is synonymous with CCL4, SCYA4, and MIP1B, while LAG1 is synonymous with CCL4L and SCYA4L.
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]
Colobran, R., Adreani, P., Ashhab, Y., Llano, A., Este, J. A., Dominguez, O., Pujol-Borrell, R., Juan, M. Multiple products derived from two CCL4 loci: high incidence of a new polymorphism in HIV-positive patients. J. Immun. 174: 5655-5664, 2005. [PubMed: 15843566] [Full Text: https://doi.org/10.4049/jimmunol.174.9.5655]
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]
Kamin-Lewis, R., Abdelwahab, S. F., Trang, C., Baker, A., DeVico, A. L., Gallo, R. C., Lewis, G. K. Perforin-low memory CD8+ cells are the predominant T cells in normal humans that synthesize the beta-chemokine macrophage inflammatory protein-1-beta. Proc. Nat. Acad. Sci. 98: 9283-9288, 2001. [PubMed: 11470920] [Full Text: https://doi.org/10.1073/pnas.161298998]
Lipes, M. A., Napolitano, M., Jeang, K.-T., Chang, N. T., Leonard, W. J. Identification, cloning, and characterization of an immune activation gene. Proc. Nat. Acad. Sci. 85: 9704-9708, 1988. [PubMed: 2462251] [Full Text: https://doi.org/10.1073/pnas.85.24.9704]
Lu, J., Honczarenko, M., Sloan, S. R. Independent expression of the two paralogous CCL4 genes in monocytes and B lymphocytes. Immunogenetics 55: 706-711, 2004. [PubMed: 14673550] [Full Text: https://doi.org/10.1007/s00251-003-0636-z]
Modi, W. S., Bergeron, J., Sanford, M. The human MIP-1-beta chemokine is encoded by two paralogous genes, ACT-2 and LAG-1. Immunogenetics 53: 543-549, 2001. [PubMed: 11685466] [Full Text: https://doi.org/10.1007/s002510100366]
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]
Modi, W. S., Napolitano, M., Cevario, S. J., Gnarra, J. R., Seuanez, H. N., Leonard, W. J. Chromosomal localization of the ACT-2 cytokine. (Abstract) Cytogenet. Cell Genet. 58: 2008 only, 1991.
Napolitano, M., Modi, W. S., Cevario, S. J., Gnarra, J. R., Seuanez, H. N., Leonard, W. J. The gene encoding the Act-2 cytokine: genomic structure, HTLV-I/Tax responsiveness of 5-prime upstream sequences, and chromosomal localization. J. Biol. Chem. 266: 17531-17536, 1991. [PubMed: 1894635]
Tasaki, Y., Fukuda, S., Iio, M., Miura, R., Imai, T., Sugano, S., Yoshie, O., Hughes, A. L., Nomiyama, H. Chemokine PARC gene (SCYA18) generated by fusion of two MIP-1-alpha/LD78-alpha-like genes. Genomics 55: 353-357, 1999. [PubMed: 10049593] [Full Text: https://doi.org/10.1006/geno.1998.5670]