Chemokine (C-C motif) ligands 4 (also CCL4) previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the CCL4gene.[2]CCL4 belongs to a cluster of genes located on 17q11-q21 of the chromosomal region.[3] Identification and localization of the gene on the chromosome 17 was 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 small cytokine that belongs to the CC chemokine subfamily. CCL4 is being secreted under mitogenic signals and antigens and hereby acts as a chemoattractant for natural killer cells, monocytes and various other immune cells in the site of inflamed or damaged tissue.[5]
In the human genome, CCL4 and many other CC chemokines is encoded by a single gene on chromosome 17 (17q11-q21). The CCL4 gene consists of three exons and two introns which 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 CCL4 protein precursor consist of 92 amino 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]
CCL4 is a polypeptide chain with a molecular weight of 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]
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.
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]
^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.
^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.
^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-3alpha/CCL20 in human B cells". Blood. 96 (7): 2338–2345. doi:10.1182/blood.v96.7.2338.h8002338_2338_2345. PMID11001880.
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, 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.
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.
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.
