CCL2

In the human genome, CCL2 and many other CC chemokines are located on chromosome 17 (17q11.2-q21.1).{{cite journal | vauthors = Mehrabian M, Sparkes RS, Mohandas T, Fogelman AM, Lusis AJ | title = Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11.2-q21.1 | journal = Genomics | volume = 9 | issue = 1 | pages = 200–3 | date = January 1991 | pmid = 2004761 | doi = 10.1016/0888-7543(91)90239-B }} The gene span is 1,927 bases and the CCL2 gene resides on the Watson (plus) strand. The CCL2 gene has three exons and two introns. The CCL2 protein precursor contains a signal peptide of 23 amino acids. In turn, the mature CCL2 is 76 amino acids long.{{cite journal | vauthors = Yoshimura T, Yuhki N, Moore SK, Appella E, Lerman MI, Leonard EJ | title = Human monocyte chemoattractant protein-1 (MCP-1). Full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE | journal = FEBS Letters | volume = 244 | issue = 2 | pages = 487–93 | date = February 1989 | pmid = 2465924 | doi = 10.1016/0014-5793(89)80590-3 | s2cid = 7097272 | doi-access = free | bibcode = 1989FEBSL.244..487Y }}{{cite journal | vauthors = Furutani Y, Nomura H, Notake M, Oyamada Y, Fukui T, Yamada M, Larsen CG, Oppenheim JJ, Matsushima K | title = Cloning and sequencing of the cDNA for human monocyte chemotactic and activating factor (MCAF) | journal = Biochemical and Biophysical Research Communications | volume = 159 | issue = 1 | pages = 249–55 | date = February 1989 | pmid = 2923622 | doi = 10.1016/0006-291X(89)92430-3 | url = https://zenodo.org/record/1253804 }} 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.{{cite journal | vauthors = 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 | title = CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study | journal = Circulation | volume = 112 | issue = 8 | pages = 1113–20 | date = August 2005 | pmid = 16116069 | doi = 10.1161/CIRCULATIONAHA.105.543579 | s2cid = 12320863 }}{{cite journal | vauthors = Bielinski SJ, Pankow JS, Miller MB, Hopkins PN, Eckfeldt JH, Hixson J, Liu Y, Register T, Myers RH, Arnett DK | title = Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI family heart study follow-up examination | journal = Genes and Immunity | volume = 8 | issue = 8 | pages = 684–90 | date = December 2007 | pmid = 17917677 | doi = 10.1038/sj.gene.6364434 | s2cid = 8242432 | doi-access = free }}

CCL2 is a monomeric polypeptide, with a molecular weight of approximately 13-15 kDa depending on levels of glycosylation.{{cite journal |last1=Yoshimura |first1=T |title=The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally? |journal=Cellular & Molecular Immunology |date=April 2018 |volume=15 |issue=4 |pages=335–345 |doi=10.1038/cmi.2017.135 |pmid=29375123|pmc=6052833 }} CCL2 is anchored in the plasma membrane of endothelial cells by glycosaminoglycan side chains of proteoglycans. CCL2 is primarily secreted by monocytes, macrophages and dendritic cells. Platelet derived growth factor is a major inducer of CCL2 gene.

CCR2 and CCR4 are two cell surface receptors that bind CCL2.{{cite journal | vauthors = Craig MJ, Loberg RD | title = CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases | journal = Cancer and Metastasis Reviews | volume = 25 | issue = 4 | pages = 611–9 | date = December 2006 | pmid = 17160712 | doi = 10.1007/s10555-006-9027-x | s2cid = 24366011 }}

CCL2 exhibits a chemotactic activity for monocytes and basophils. However, it does not attract neutrophils or

eosinophils. 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.{{cite journal | vauthors = Conti P, Boucher W, Letourneau R, Feliciani C, Reale M, Barbacane RC, Vlagopoulos P, Bruneau G, Thibault J, Theoharides TC | title = Monocyte chemotactic protein-1 provokes mast cell aggregation and [3H]5HT release | journal = Immunology | volume = 86 | issue = 3 | pages = 434–40 | date = November 1995 | pmid = 8550082 | pmc = 1383948 }}{{cite journal | vauthors = Bischoff SC, Krieger M, Brunner T, Dahinden CA | title = Monocyte chemotactic protein 1 is a potent activator of human basophils | journal = The Journal of Experimental Medicine | volume = 175 | issue = 5 | pages = 1271–5 | date = May 1992 | pmid = 1569397 | pmc = 2119199 | doi = 10.1084/jem.175.5.1271 }} CCL2 augments monocyte anti-tumor activity and it is essential for formation of granulomas. CCL2 protein become a CCR2 antagonist when it is cleaved by metalloproteinase MMP-12.{{cite journal | vauthors = Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM | title = Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx | journal = Blood | volume = 112 | issue = 8 | pages = 3455–64 | date = October 2008 | pmid = 18660381 | doi = 10.1182/blood-2007-12-129080 | s2cid = 25944573 | doi-access = free }}

CCL2 can be found at the sites of tooth eruption and bone degradation. In the bone, CCL2 is expressed by mature osteoclasts and osteoblasts and it is under control of nuclear factor κB (NFκB). In the human osteoclasts, CCL2 and RANTES (regulated on activation normal T cell expressed and secreted). Both MCP-1 and RANTES induce formation of TRAP-positive, multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lacked cathepsin K expression and resorptive capacity. It is proposed that CCL2 and RANTES act as autocrine loop in human osteoclast differentiation.{{cite journal | vauthors = Kim MS, Day CJ, Morrison NA | title = MCP-1 is induced by receptor activator of nuclear factor-κB ligand, promotes human osteoclast fusion, and rescues granulocyte macrophage colony-stimulating factor suppression of osteoclast formation | journal = The Journal of Biological Chemistry | volume = 280 | issue = 16 | pages = 16163–9 | date = April 2005 | pmid = 15722361 | doi = 10.1074/jbc.M412713200 | s2cid = 22756184 | doi-access = free }}

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.{{cite journal | vauthors = Banisadr G, Gosselin RD, Mechighel P, Kitabgi P, Rostène W, Parsadaniantz SM | title = Highly regionalized neuronal expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) in rat brain: evidence for its colocalization with neurotransmitters and neuropeptides | journal = The Journal of Comparative Neurology | volume = 489 | issue = 3 | pages = 275–92 | date = August 2005 | pmid = 16025454 | doi = 10.1002/cne.20598 | s2cid = 22254007 }}

CCL2 is implicated in pathogeneses of several diseases characterized by monocytic infiltrates, such as psoriasis, rheumatoid arthritis and atherosclerosis.{{cite journal | vauthors = Xia M, Sui Z | title = Recent developments in CCR2 antagonists | journal = Expert Opinion on Therapeutic Patents | volume = 19 | issue = 3 | pages = 295–303 | date = March 2009 | pmid = 19441905 | doi = 10.1517/13543770902755129 | s2cid = 45028620 }}

Administration of anti-CCL2 antibodies in a model of glomerulonephritis reduces infiltration of macrophages and T cells, reduces crescent formation, as well as scarring and renal impairment.{{cite journal | vauthors = Lloyd CM, Minto AW, Dorf ME, Proudfoot A, Wells TN, Salant DJ, Gutierrez-Ramos JC | title = RANTES and monocyte chemoattractant protein-1 (MCP-1) play an important role in the inflammatory phase of crescentic nephritis, but only MCP-1 is involved in crescent formation and interstitial fibrosis | journal = The Journal of Experimental Medicine | volume = 185 | issue = 7 | pages = 1371–80 | date = April 1997 | pmid = 9104823 | pmc = 2196251 | doi = 10.1084/jem.185.7.1371 }}

CCL2 is involved in the neuroinflammatory processes that takes place in the various diseases of the central nervous system (CNS), which are characterized by neuronal degeneration.{{cite journal | vauthors = Gerard C, Rollins BJ | title = Chemokines and disease | journal = Nature Immunology | volume = 2 | issue = 2 | pages = 108–15 | date = February 2001 | pmid = 11175802 | doi = 10.1038/84209 | s2cid = 28336866 }} CCL2 expression in glial cells is increased in epilepsy,{{cite journal | vauthors = Foresti ML, Arisi GM, Katki K, Montañez A, Sanchez RM, Shapiro LA | title = Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus | journal = Journal of Neuroinflammation | volume = 6 | pages = 40 | date = December 2009 | pmid = 20034406 | pmc = 2804573 | doi = 10.1186/1742-2094-6-40 | doi-access = free }}{{cite journal | vauthors = Fabene PF, Bramanti P, Constantin G | title = The emerging role for chemokines in epilepsy | journal = Journal of Neuroimmunology | volume = 224 | issue = 1–2 | pages = 22–7 | date = July 2010 | pmid = 20542576 | doi = 10.1016/j.jneuroim.2010.05.016 | s2cid = 5121343 }} brain ischemia{{cite journal | vauthors = Kim JS, Gautam SC, Chopp M, Zaloga C, Jones ML, Ward PA, Welch KM | title = Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat | journal = Journal of Neuroimmunology | volume = 56 | issue = 2 | pages = 127–34 | date = February 1995 | pmid = 7860708 | doi = 10.1016/0165-5728(94)00138-e | s2cid = 45538922 }} Alzheimer's disease{{cite journal | vauthors = Hickman SE, El Khoury J | title = Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease | journal = CNS & Neurological Disorders Drug Targets | volume = 9 | issue = 2 | pages = 168–73 | date = April 2010 | pmid = 20205643 | pmc = 3684802 | doi = 10.2174/187152710791011982 }} experimental autoimmune encephalomyelitis (EAE),{{cite journal | vauthors = Ransohoff RM, Hamilton TA, Tani M, Stoler MH, Shick HE, Major JA, Estes ML, Thomas DM, Tuohy VK | title = Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis | journal = FASEB Journal | volume = 7 | issue = 6 | pages = 592–600 | date = April 1993 | pmid = 8472896 | doi = 10.1096/fasebj.7.6.8472896 | doi-access = free | s2cid = 13552110 }} and traumatic brain injury.{{cite journal | vauthors = Semple BD, Bye N, Rancan M, Ziebell JM, Morganti-Kossmann MC | title = Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 30 | issue = 4 | pages = 769–82 | date = April 2010 | pmid = 20029451 | pmc = 2949175 | doi = 10.1038/jcbfm.2009.262 }}

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.{{cite journal | vauthors = Liu ZH, Chen LL, Deng XL, Song HJ, Liao YF, Zeng TS, Zheng J, Li HQ | title = Methylation status of CpG sites in the MCP-1 promoter is correlated to serum MCP-1 in Type 2 diabetes | journal = Journal of Endocrinological Investigation | volume = 35 | issue = 6 | pages = 585–9 | date = June 2012 | pmid = 21975431 | doi = 10.3275/7981 | s2cid = 14613351 }}

CCL2 induces amylin expression through ERK1/ERK2/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. Amylin upregulation by CCL2 contributes to the elevation of the plasma amylin and insulin resistance in obesity.{{cite journal | vauthors = Cai K, Qi D, Hou X, Wang O, Chen J, Deng B, Qian L, Liu X, Le Y | title = MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2 | journal = PLOS ONE | volume = 6 | issue = 5 | pages = e19559 | date = May 2011 | pmid = 21589925 | pmc = 3092759 | doi = 10.1371/journal.pone.0019559 | bibcode = 2011PLoSO...619559C | editor1-last = Fadini | editor1-first = Gian Paolo | doi-access = free }}

Adipocytes secrete various adipokines 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 in myocytes. 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.{{cite journal | vauthors = Sell H, Dietze-Schroeder D, Kaiser U, Eckel J | title = Monocyte chemotactic protein-1 is a potential player in the negative cross-talk between adipose tissue and skeletal muscle | journal = Endocrinology | volume = 147 | issue = 5 | pages = 2458–67 | date = May 2006 | pmid = 16439461 | doi = 10.1210/en.2005-0969 | doi-access = free }}

Incubation of HL-1 cardiomyocytes and human myocytes with oxidized-LDL induced the expression of BNP and CCL2 genes, while native LDL (N-LDL) had no effect.{{cite journal | vauthors = Chandrakala AN, Sukul D, Selvarajan K, Sai-Sudhakar C, Sun B, Parthasarathy S | title = Induction of brain natriuretic peptide and monocyte chemotactic protein-1 gene expression by oxidized low-density lipoprotein: relevance to ischemic heart failure | journal = American Journal of Physiology. Cell Physiology | volume = 302 | issue = 1 | pages = C165-77 | date = January 2012 | pmid = 21900689 | doi = 10.1152/ajpcell.00116.2011 | s2cid = 9801961 }}

Treatment with melatonin in old mice with age related liver inflammation decreased the mRNA expression of TNF-α, IL-1β, HO (HO-1 and HO-2), iNOS, CCL2, NF-κB1, NF-κB2 and NKAP in old male mice. The protein expression of TNF-α, IL-1β was also decreased and IL-10 increased with melatonin treatment. Exogenous administration of melatonin was able to reduce inflammation.{{cite journal | vauthors = Cuesta S, Kireev R, Forman K, García C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA | title = Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8) | journal = Experimental Gerontology | volume = 45 | issue = 12 | pages = 950–6 | date = December 2010 | pmid = 20817086 | doi = 10.1016/j.exger.2010.08.016 | s2cid = 42491323 }}

{{Reflist|33em}}

• {{UCSC gene info|CCL2}}

{{Refbegin|33em}}

• {{cite book | vauthors = Yoshimura T, Leonard EJ | title = Chemotactic Cytokines | chapter = Human Monocyte Chemoattractant Protein-1 (MCP-1) | series = Advances in Experimental Medicine and Biology | volume = 305 | pages = 47–56 | year = 1991 | pmid = 1661560 | doi = 10.1007/978-1-4684-6009-4_6 | isbn = 978-1-4684-6011-7 }}
• {{cite journal | vauthors = Wahl SM, Greenwell-Wild T, Hale-Donze H, Moutsopoulos N, Orenstein JM | title = Permissive factors for HIV-1 infection of macrophages | journal = Journal of Leukocyte Biology | volume = 68 | issue = 3 | pages = 303–10 | date = September 2000 | doi = 10.1189/jlb.68.3.303 | pmid = 10985244 | s2cid = 41684404 }}
• {{cite journal | vauthors = Sell H, Eckel J | title = Monocyte chemotactic protein-1 and its role in insulin resistance | journal = Current Opinion in Lipidology | volume = 18 | issue = 3 | pages = 258–62 | date = June 2007 | pmid = 17495598 | doi = 10.1097/MOL.0b013e3281338546 | s2cid = 33827660 }}

{{Refend}}

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{{Chemokine receptor modulators}}

{{DEFAULTSORT:Ccl2}}

Category:Cytokines