CCL4
CCL4L1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | CCL4L1,AT744.2, CCL4L, LAG-1, LAG1, SCYA4L, SCYA4L1, MIP-1-beta, SCYA4L2, C-C motif chemokine ligand 4 like 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM:603782;GeneCards:CCL4L1;OMA:CCL4L1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Chemokine (C-C motif) ligands 4(alsoCCL4) previously known asmacrophage inflammatory protein(MIP-1β), is aproteinwhich in humans is encoded by theCCL4gene.[2]CCL4belongs to a cluster of genes located on 17q11-q21 of the chromosomal region.[3]Identification and localization of the gene on thechromosome 17was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.[4]
CCL4 is a smallcytokinethat belongs to the CCchemokinesubfamily. CCL4 is being secreted under mitogenic signals and antigens and hereby acts as a chemoattractant fornatural killer cells,monocytes and various other immune cells in the site of inflamed or damaged tissue.[5]
Genomics
[edit]In the human genome, CCL4 and many other CC chemokines is encoded by a single gene onchromosome 17(17q11-q21). The CCL4 gene consists of threeexonsand twointronswhich are separated by 14 kb and are organized in a head to head fashion. MIP-1 genes have 3 untranslated gene regions containing a polyadenylation site (AATAAA) and several AT-rich sequences.[6]The CCL4protein precursorconsist of 92amino acids.In turn, the mature CCL4 protein is 92 amino acids long. The CCL4 predicted Mr weight is 7814.8 Da with no apparent N-linked glycosylation site as in other of the MIP-1 proteins.[7][8][9]
![](https://upload.wikimedia.org/wikipedia/commons/thumb/0/02/Protein_CCL4_PDB_1hum.png/318px-Protein_CCL4_PDB_1hum.png)
Molecular structure
[edit]CCL4 is a polypeptide chain with amolecular weightof approximately 8-10 kDa[10]arranged in a three-dimensional structure in the form of as symmetrical homodimer.
Monomeric subunits in their secondary structure composed by a triple-stranded antiparallel sheet form in a Greek key structure on top of which lies an α-helix. NH2-terminus is arranged as a long loop followed by a four-residue helical turn. The overall form of homodimer is globular elongated and cylindrical with sizes: 56 Å × 30 Å × 26 Å in contrast of monomer structure which is similar to IL-8.[10][11]
CCL4 as well as other MIP-1s whether human or mouse have a high tendency to self-aggregation. Aggregation as a reversible and dynamic process depends largely on the concentration of chemokine.[12]
The distinction between the CC chemokine families, MIP-1α and MIP-1β, was initially based on whether the first two cysteine residues are separated by one residue (α) or are adjacent (β).[10]Final form of tertiary structure structure of MIP-1 has been defined by heteronuclear magnetic resonance (NMR) analysis.
Concentration of this chemokine has been shown to be inversely related with MicroRNA-125b. Concentration of CCL4 within the body increases with age, which may cause chronic inflammation and liver damage.[13][14]
Function
[edit]CCL4 as a chemokine which is produced during inflammation, damage or other important dynamic processes as an angiogenesis to attract immune cells as leukocytes transgress the vascular endothelium and migrate into peripheral tissues.
Production of CCL4
CCL4 is produced by:monocytes,B cells,T cells,NK cells,dendritic cells,neutrophils,fibroblasts,endothelial cellssuch as vascular smooth muscle cells, brain microvessel endothelial cells, fetalmicrogliaand epithelial cells.
- Monocytes produce high amounts of CCL4 when they are stimulated with LPS or IL-7 and production is suppressed by IL-4.[15]
- T cells and B cells secrete CCL4 response to Ag receptor (BCR) triggering.[16]
- NK cells produce CCL4 in response to stimulation with IL-2, physiological activation signals such as lysis. NK cells can be important source of CC chemokines and may suppress HIV infection by inhibition replication of HIV-1 virus by interfering with the ability to utilize CCR5 as a coreceptor for entry in CD4(+) cells.[17]
- Dendritic cells secrete and respond to chemokines after stimulation to LPS, TNFα, or CD40 ligand. In maturing of DC production of chemokines have different impact on chemokine receptor function: CCR1 and CCR5 were down-regulated whereas CCR7 were stimulated increased in maturing DC. Production of chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other cells.[18]
- Neutrophils produce CCL4 in the presence of IFN-gamma and its inhibition by IL-10.[19]
- Endothelial cells release CCL4 following stimulation with LPS, TNFα, IFN-, or IL-1.[20]
CCL4 is a major HIV-suppressive factor produced by CD8+ T cells.[21]
Perforin-low memory CD8+ T cells that normally synthesize MIP-1-beta.[22]
CCL4 is produced by: neutrophils, monocytes, B cells, T cells, fibroblasts, endothelial cells, and epithelial cells.[13]
Interactions
[edit]CCL4 has been shown tointeractwithCCL3.[23]
CCL4 binds to G protein-Coupled ReceptorsCCR5andCCR8.[13]
See also
[edit]References
[edit]- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^Irving SG, Zipfel PF, Balke J, McBride OW, Morton CC, Burd PR, et al. (June 1990)."Two inflammatory mediator cytokine genes are closely linked and variably amplified on chromosome 17q".Nucleic Acids Research.18(11): 3261–3270.doi:10.1093/nar/18.11.3261.PMC330932.PMID1972563.
- ^Hu GN, Tzeng HE, Chen PC, Wang CQ, Zhao YM, Wang Y, et al. (2018)."Correlation betweenCCL4gene polymorphisms and clinical aspects of breast cancer ".International Journal of Medical Sciences.15(11): 1179–1186.doi:10.7150/ijms.26771.PMC6097259.PMID30123055.
- ^Wolpe SD, Davatelis G, Sherry B, Beutler B, Hesse DG, Nguyen HT, et al. (February 1988)."Macrophages secrete a novel heparin-binding protein with inflammatory and neutrophil chemokinetic properties".The Journal of Experimental Medicine.167(2): 570–581.doi:10.1084/jem.167.2.570.PMC2188834.PMID3279154.
- ^Menten P, Wuyts A, Van Damme J (December 2002). "Macrophage inflammatory protein-1".Cytokine & Growth Factor Reviews.13(6): 455–481.doi:10.1016/s1359-6101(02)00045-x.PMID12401480.
- ^Menten P, Wuyts A, Van Damme J (December 2002). "Macrophage inflammatory protein-1".Cytokine & Growth Factor Reviews.13(6): 455–481.doi:10.1016/S1359-6101(02)00045-X.PMID12401480.
- ^Hirashima M, Ono T, Nakao M, Nishi H, Kimura A, Nomiyama H, et al. (January 1992). "Nucleotide sequence of the third cytokine LD78 gene and mapping of all three LD78 gene loci to human chromosome 17".DNA Sequence.3(4): 203–212.doi:10.3109/10425179209034019.PMID1296815.
- ^Lipes MA, Napolitano M, Jeang KT, Chang NT, Leonard WJ (December 1988)."Identification, cloning, and characterization of an immune activation gene".Proceedings of the National Academy of Sciences of the United States of America.85(24): 9704–9708.Bibcode:1988PNAS...85.9704L.doi:10.1073/pnas.85.24.9704.PMC282843.PMID2462251.
- ^Koopmann W, Krangel MS (April 1997)."Identification of a glycosaminoglycan-binding site in chemokine macrophage inflammatory protein-1 Alpha".The Journal of Biological Chemistry.272(15): 10103–10109.doi:10.1074/jbc.272.15.10103.PMID9092555.
- ^abcLodi PJ, Garrett DS, Kuszewski J, Tsang ML, Weatherbee JA, Leonard WJ, et al. (March 1994)."High-resolution solution structure of the beta chemokine hMIP-1 beta by multidimensional NMR".Science.263(5154): 1762–1767.Bibcode:1994Sci...263.1762L.doi:10.1126/science.8134838.PMID8134838.
- ^Czaplewski LG, McKeating J, Craven CJ, Higgins LD, Appay V, Brown A, et al. (June 1999)."Identification of amino acid residues critical for aggregation of human CC chemokines macrophage inflammatory protein (MIP)-1 Alpha, MIP-1beta, and RANTES. Characterization of active disaggregated chemokine variants".The Journal of Biological Chemistry.274(23): 16077–16084.doi:10.1074/jbc.274.23.16077.PMID10347159.
- ^Nibbs RJ, Graham GJ, Pragnell IB (1998). "Macrophage Inflammatory Protein 1-α".Cytokines.Elsevier. pp. 467–488.
- ^abcCheng NL, Chen X, Kim J, Shi AH, Nguyen C, Wersto R, Weng NP (April 2015)."MicroRNA-125b modulates inflammatory chemokine CCL4 expression in immune cells and its reduction causes CCL4 increase with age".Aging Cell.14(2): 200–208.doi:10.1111/acel.12294.PMC4364832.PMID25620312.
- ^Morimoto T, Takagi H, Kondo T (January 1985). "Canine pancreatic allotransplantation with duodenum (pancreaticoduodenal transplantation) using cyclosporin A".Nagoya Journal of Medical Science.47(1–2): 57–66.PMID3887178.
- ^Weinberg JB, Mason SN, Wortham TS (June 1992)."Inhibition of tumor necrosis factor- Alpha (TNF- Alpha ) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin-induced TNF- Alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation".Blood.79(12): 3337–3343.doi:10.1182/blood.v79.12.3337.3337.PMID1596574.
- ^Krzysiek R, Lefevre EA, Bernard J, Foussat A, Galanaud P, Louache F, Richard Y (October 2000). "Regulation of CCR6 chemokine receptor expression and responsiveness to macrophage inflammatory protein-3 Alpha /CCL20 in human B cells".Blood.96(7): 2338–2345.doi:10.1182/blood.v96.7.2338.h8002338_2338_2345.PMID11001880.
- ^Oliva A, Kinter AL, Vaccarezza M, Rubbert A, Catanzaro A, Moir S, et al. (July 1998)."Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro".The Journal of Clinical Investigation.102(1): 223–231.doi:10.1172/jci2323.PMC509084.PMID9649576.
- ^Sallusto F, Palermo B, Lenig D, Miettinen M, Matikainen S, Julkunen I, et al. (May 1999)."Distinct patterns and kinetics of chemokine production regulate dendritic cell function".European Journal of Immunology.29(5): 1617–1625.doi:10.1002/(sici)1521-4141(199905)29:05<1617::aid-immu1617>3.0.co;2-3.PMID10359116.S2CID13766954.
- ^Lapinet JA, Scapini P, Calzetti F, Pérez O, Cassatella MA (December 2000)."Gene expression and production of tumor necrosis factor Alpha, interleukin-1beta (IL-1beta), IL-8, macrophage inflammatory protein 1 Alpha (MIP-1 Alpha ), MIP-1beta, and gamma interferon-inducible protein 10 by human neutrophils stimulated with group B meningococcal outer membrane vesicles".Infection and Immunity.68(12): 6917–6923.doi:10.1128/iai.68.12.6917-6923.2000.PMC97799.PMID11083814.
- ^Shukaliak JA, Dorovini-Zis K (May 2000)."Expression of the beta-chemokines RANTES and MIP-1 beta by human brain microvessel endothelial cells in primary culture".Journal of Neuropathology and Experimental Neurology.59(5): 339–352.doi:10.1093/jnen/59.5.339.PMID10888363.
- ^Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P (December 1995)."Identification of RANTES, MIP-1 Alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells".Science.270(5243): 1811–1815.Bibcode:1995Sci...270.1811C.doi:10.1126/science.270.5243.1811.PMID8525373.S2CID84062618.
- ^Kamin-Lewis R, Abdelwahab SF, Trang C, Baker A, DeVico AL, Gallo RC, Lewis GK (July 2001)."Perforin-low memory CD8+ cells are the predominant T cells in normal humans that synthesize the beta -chemokine macrophage inflammatory protein-1beta".Proceedings of the National Academy of Sciences of the United States of America.98(16): 9283–9288.Bibcode:2001PNAS...98.9283K.doi:10.1073/pnas.161298998.PMC55412.PMID11470920.
- ^Guan E, Wang J, Norcross MA (April 2001)."Identification of human macrophage inflammatory proteins 1 Alpha and 1beta as a native secreted heterodimer".The Journal of Biological Chemistry.276(15): 12404–12409.doi:10.1074/jbc.M006327200.PMID11278300.
Further reading
[edit]- Menten P, Wuyts A, Van Damme J (December 2002). "Macrophage inflammatory protein-1".Cytokine & Growth Factor Reviews.13(6): 455–481.doi:10.1016/S1359-6101(02)00045-X.PMID12401480.
- Muthumani K, Desai BM, Hwang DS, Choo AY, Laddy DJ, Thieu KP, et al. (April 2004). "HIV-1 Vpr and anti-inflammatory activity".DNA and Cell Biology.23(4): 239–247.doi:10.1089/104454904773819824.PMID15142381.
- Conti L, Fantuzzi L, Del Cornò M, Belardelli F, Gessani S (2005). "Immunomodulatory effects of the HIV-1 gp120 protein on antigen presenting cells: implications for AIDS pathogenesis".Immunobiology.209(1–2): 99–115.doi:10.1016/j.imbio.2004.02.008.PMID15481145.
- Joseph AM, Kumar M, Mitra D (January 2005). "Nef:" necessary and enforcing factor "in HIV infection".Current HIV Research.3(1): 87–94.doi:10.2174/1570162052773013.PMID15638726.
- Zhao RY, Elder RT (March 2005)."Viral infections and cell cycle G2/M regulation".Cell Research.15(3): 143–149.doi:10.1038/sj.cr.7290279.PMID15780175.
- Zhao RY, Bukrinsky M, Elder RT (April 2005). "HIV-1 viral protein R (Vpr) & host cellular responses".The Indian Journal of Medical Research.121(4): 270–286.PMID15817944.
- Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY (2006)."Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions".Cell Research.15(11–12): 923–934.doi:10.1038/sj.cr.7290370.PMID16354571.
- King JE, Eugenin EA, Buckner CM, Berman JW (April 2006)."HIV tat and neurotoxicity".Microbes and Infection.8(5): 1347–1357.doi:10.1016/j.micinf.2005.11.014.PMID16697675.
- Napolitano M, Modi WS, Cevario SJ, Gnarra JR, Seuanez HN, Leonard WJ (September 1991)."The gene encoding the Act-2 cytokine. Genomic structure, HTLV-I/Tax responsiveness of 5' upstream sequences, and chromosomal localization".The Journal of Biological Chemistry.266(26): 17531–17536.doi:10.1016/S0021-9258(19)47404-8.PMID1894635.
- Irving SG, Zipfel PF, Balke J, McBride OW, Morton CC, Burd PR, et al. (June 1990)."Two inflammatory mediator cytokine genes are closely linked and variably amplified on chromosome 17q".Nucleic Acids Research.18(11): 3261–3270.doi:10.1093/nar/18.11.3261.PMC330932.PMID1972563.
- Baixeras E, Roman-Roman S, Jitsukawa S, Genevee C, Mechiche S, Viegas-Pequignot E, et al. (November 1990). "Cloning and expression of a lymphocyte activation gene (LAG-1)".Molecular Immunology.27(11): 1091–1102.doi:10.1016/0161-5890(90)90097-J.PMID2247088.
- Lipes MA, Napolitano M, Jeang KT, Chang NT, Leonard WJ (December 1988)."Identification, cloning, and characterization of an immune activation gene".Proceedings of the National Academy of Sciences of the United States of America.85(24): 9704–9708.Bibcode:1988PNAS...85.9704L.doi:10.1073/pnas.85.24.9704.PMC282843.PMID2462251.
- Brown KD, Zurawski SM, Mosmann TR, Zurawski G (January 1989). "A family of small inducible proteins secreted by leukocytes are members of a new superfamily that includes leukocyte and fibroblast-derived inflammatory agents, growth factors, and indicators of various activation processes".Journal of Immunology.142(2): 679–687.PMID2521353.
- Zipfel PF, Balke J, Irving SG, Kelly K, Siebenlist U (March 1989). "Mitogenic activation of human T cells induces two closely related genes which share structural similarities with a new family of secreted factors".Journal of Immunology.142(5): 1582–1590.PMID2521882.
- Chang HC, Reinherz EL (June 1989). "Isolation and characterization of a cDNA encoding a putative cytokine which is induced by stimulation via the CD2 structure on human T lymphocytes".European Journal of Immunology.19(6): 1045–1051.doi:10.1002/eji.1830190614.PMID2568930.S2CID35270650.
- Miller MD, Hata S, De Waal Malefyt R, Krangel MS (November 1989). "A novel polypeptide secreted by activated human T lymphocytes".Journal of Immunology.143(9): 2907–2916.PMID2809212.
- Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, et al. (September 1995). "Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence".Nature.377(6547 Suppl): 3–174.PMID7566098.
- Post TW, Bozic CR, Rothenberg ME, Luster AD, Gerard N, Gerard C (December 1995). "Molecular characterization of two murine eosinophil beta chemokine receptors".Journal of Immunology.155(11): 5299–5305.PMID7594543.
- Combadiere C, Ahuja SK, Murphy PM (July 1995)."Cloning and functional expression of a human eosinophil CC chemokine receptor".The Journal of Biological Chemistry.270(28): 16491–16494.doi:10.1074/jbc.270.28.16491.PMID7622448.
- Paolini JF, Willard D, Consler T, Luther M, Krangel MS (September 1994). "The chemokines IL-8, monocyte chemoattractant protein-1, and I-309 are monomers at physiologically relevant concentrations".Journal of Immunology.153(6): 2704–2717.PMID8077676.
External links
[edit]- HumanCCL4genome location andCCL4gene details page in theUCSC Genome Browser.