This article is about the gene and protein. For CCL2, the FAA airport code, seeCandle Lake Airpark. For CCl2, the diradical compound, seeDichlorocarbene.
Thechemokine (C-C motif) ligand 2 (CCL2) is also referred to asmonocyte chemoattractant protein 1 (MCP1) andsmall inducible cytokine A2. CCL2 is a smallcytokine that belongs to theCC chemokine family. CCL2 tightly regulates cellular mechanics[5] and thereby recruitsmonocytes,memory T cells, anddendritic cells to the sites ofinflammation produced by either tissue injury orinfection.[6][7]
In thehuman genome, CCL2 and many other CC chemokines are located onchromosome 17 (17q11.2-q21.1).[8] The gene span is 1,927 bases and the CCL2 gene resides on the Watson (plus) strand. The CCL2 gene has threeexons and twointrons. The CCL2protein precursor contains a signal peptide of 23amino acids. In turn, the mature CCL2 is 76 amino acids long.[9][10] The CCL2 predicted weight is 11.025 kilodaltons (kDa).
In humans, the levels of CCL2 can vary considerably. In the white people of European descent, the multivariable-adjusted heritability of CCL2 concentrations is as much as 0.37 in the blood plasma and 0.44 - in the serum.[11][12]
CCR2 andCCR4 are two cell surface receptors that bind CCL2.[14]
CCL2 exhibits a chemotactic activity for monocytes and basophils. However, it does not attract neutrophils oreosinophils. After deletion of the N-terminal residue, CCL2 loses its attractivity for basophils and becomes a chemoattractant of eosinophils. Basophils and mast cells that are treated with CCL2 release their granules to the intercellular space. This effect can be also potentiated by a pre-treatment with IL-3 or even by other cytokines.[15][16] CCL2 augments monocyte anti-tumor activity and it is essential for formation of granulomas. CCL2 protein become aCCR2 antagonist when it is cleaved bymetalloproteinase MMP-12.[17]
CCL2 can be found at the sites of tooth eruption and bone degradation. In the bone, CCL2 is expressed by matureosteoclasts andosteoblasts and it is under control of nuclear factor κB (NFκB). In the human osteoclasts, CCL2 andRANTES (regulated on activation normal T cell expressed and secreted). Both MCP-1 and RANTES induce formation ofTRAP-positive, multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lackedcathepsin K expression and resorptive capacity. It is proposed that CCL2 and RANTES act asautocrine loop in human osteoclastdifferentiation.[18]
The CCL2 chemokine is also expressed by neurons, astrocytes and microglia. The expression of CCL2 in neurons is mainly found in the cerebral cortex, globus pallidus, hippocampus, paraventricular and supraoptic hypothalamic nuclei, lateral hypothalamus, substantia nigra, facial nuclei, motor and spinal trigeminal nuclei, gigantocellular reticular nucleus and in Purkinje cells in the cerebellum.[19]
Administration of anti-CCL2 antibodies in a model ofglomerulonephritis reduces infiltration of macrophages and T cells, reduces crescent formation, as well as scarring and renal impairment.[21]
Hypomethylation of CpG sites within the CCL2 promoter region is affected by high levels of blood glucose and TG, which increase CCL2 levels in the blood serum. The latter plays an important role in the vascular complications of type 2 diabetes.[29]
CCL2 inducesamylin expression throughERK1/ERK2/JNK-AP1 andNF-κB related signaling pathways independent ofCCR2. Amylin upregulation by CCL2 contributes to the elevation of the plasma amylin and insulin resistance in obesity.[30]
Adipocytes secrete variousadipokines that may be involved in the negative cross-talk between adipose tissue and skeletal muscle. CCL2 impairs insulin signaling in skeletal muscle cells via ERK1/2 activation at doses similar to its physiological plasma concentrations (200 pg/mL), but does not involve activation of the NF-κB pathway. CCL2 significantly reduced insulin-stimulated glucose uptake inmyocytes. CCL2 may represent a molecular link in the negative cross-talk between adipose tissue and skeletal muscle assigning a completely novel important role to CCL2 besides inflammation.[31]
Incubation of HL-1cardiomyocytes and human myocytes with oxidized-LDL induced the expression ofBNP and CCL2 genes, while native LDL (N-LDL) had no effect.[32]
Treatment with melatonin in old mice with age related liver inflammation decreased the mRNA expression ofTNF-α,IL-1β, HO (HO-1 andHO-2),iNOS, CCL2,NF-κB1,NF-κB2 and NKAP in old male mice. The protein expression ofTNF-α,IL-1β was also decreased andIL-10 increased with melatonin treatment. Exogenous administration ofmelatonin was able to reduce inflammation.[33]
^Xu LL, Warren MK, Rose WL, Gong W, Wang JM (September 1996). "Human recombinant monocyte chemotactic protein and other C-C chemokines bind and induce directional migration of dendritic cells in vitro".Journal of Leukocyte Biology.60 (3):365–71.doi:10.1002/jlb.60.3.365.PMID8830793.S2CID24481789.
^Mehrabian M, Sparkes RS, Mohandas T, Fogelman AM, Lusis AJ (January 1991). "Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11.2-q21.1".Genomics.9 (1):200–3.doi:10.1016/0888-7543(91)90239-B.PMID2004761.
^McDermott DH, Yang Q, Kathiresan S, Cupples LA, Massaro JM, Keaney JF, Larson MG, Vasan RS, Hirschhorn JN, O'Donnell CJ, Murphy PM, Benjamin EJ (August 2005). "CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study".Circulation.112 (8):1113–20.doi:10.1161/CIRCULATIONAHA.105.543579.PMID16116069.S2CID12320863.
^Banisadr G, Gosselin RD, Mechighel P, Kitabgi P, Rostène W, Parsadaniantz SM (August 2005). "Highly regionalized neuronal expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) in rat brain: evidence for its colocalization with neurotransmitters and neuropeptides".The Journal of Comparative Neurology.489 (3):275–92.doi:10.1002/cne.20598.PMID16025454.S2CID22254007.
^Kim JS, Gautam SC, Chopp M, Zaloga C, Jones ML, Ward PA, Welch KM (February 1995). "Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat".Journal of Neuroimmunology.56 (2):127–34.doi:10.1016/0165-5728(94)00138-e.PMID7860708.S2CID45538922.
^Chandrakala AN, Sukul D, Selvarajan K, Sai-Sudhakar C, Sun B, Parthasarathy S (January 2012). "Induction of brain natriuretic peptide and monocyte chemotactic protein-1 gene expression by oxidized low-density lipoprotein: relevance to ischemic heart failure".American Journal of Physiology. Cell Physiology.302 (1): C165-77.doi:10.1152/ajpcell.00116.2011.PMID21900689.S2CID9801961.
^Cuesta S, Kireev R, Forman K, García C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA (December 2010). "Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8)".Experimental Gerontology.45 (12):950–6.doi:10.1016/j.exger.2010.08.016.PMID20817086.S2CID42491323.
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