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''For the ICAO airport code see [[Candle Lake Airpark]], for the diradical compound see [[Dichlorocarbene]].''
''For the ICAO airport code see [[Candle Lake Airpark]], for the diradical compound see [[Dichlorocarbene]].''
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{{Infobox_gene}}
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| update_page = yes
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{{GNF_Protein_box
| image = PBB_Protein_CCL2_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1dok.
| PDB = {{PDB2|1dok}}, {{PDB2|1dol}}, {{PDB2|1dom}}, {{PDB2|1don}}, {{PDB2|1ml0}}, {{PDB2|2bdn}}
| Name = Chemokine (C-C motif) ligand 2
| HGNCid = 10618
| Symbol = CCL2
| AltSymbols =; GDCF-2; GDCF-2 HC11; HC11; HSMCR30; MCAF; MCP-1; MCP1; MGC9434; SCYA2; SMC-CF
| OMIM = 158105
| ECnumber = 
| Homologene = 2245
| MGIid = 108224
| GeneAtlas_image1 = PBB_GE_CCL2_216598_s_at_tn.png
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = 07:43, 9 October 2007 (UTC)
| Function = {{GNF_GO|id=GO:0004672 |text = protein kinase activity}} {{GNF_GO|id=GO:0004871 |text = signal transducer activity}} {{GNF_GO|id=GO:0008009 |text = chemokine activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0006874 |text = cellular calcium ion homeostasis}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006935 |text = chemotaxis}} {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0006959 |text = humoral immune response}} {{GNF_GO|id=GO:0007155 |text = cell adhesion}} {{GNF_GO|id=GO:0007187 |text = G-protein signaling, coupled to cyclic nucleotide second messenger}} {{GNF_GO|id=GO:0007259 |text = JAK-STAT cascade}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0009887 |text = organ morphogenesis}} {{GNF_GO|id=GO:0019079 |text = viral genome replication}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 6347
    | Hs_Ensembl = ENSG00000108691
    | Hs_RefseqProtein = NP_002973
    | Hs_RefseqmRNA = NM_002982
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 29606409
    | Hs_GenLoc_end = 29608329
    | Hs_Uniprot = P13500
    | Mm_EntrezGene = 20293
    | Mm_Ensembl = ENSMUSG00000035352
    | Mm_RefseqmRNA = NM_011331
    | Mm_RefseqProtein = NP_035461
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 81918040
    | Mm_GenLoc_end = 81919598
    | Mm_Uniprot = Q5SVB4
  }}
}}


'''Chemokine (C-C motif) ligand 2''' (CCL2) is a small [[cytokine]] belonging to the CC [[chemokine]] family that is also known as monocyte chemotactic protein-1 (MCP-1). It is found at the site of tooth eruption and bone degradation. In the bone, CCL2 is expressed by mature [[osteoclast]]s and [[osteoblast]]s and is under the control of nuclear factor κB (NFκB). CCL2  recruits immune cells, such as [[monocyte]]s, to sites of tissue injury and [[infection]].  This chemokine is produced as a [[protein precursor]] containing signal peptide of 23 [[amino acid]]s and a mature peptide of 76 amino acids.<ref>Yoshimura et al., 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. FEBS Lett. 1989, 244: 487-493.</ref><ref>Furutani et al., Cloning and sequencing of the cDNA for human monocyte chemotactic and activating factor (MCAF). Biochem. Biophys. Res. Commun. 159: 249-255, 1989. </ref>  It is a monomeric [[polypeptide]], with a [[molecular weight]] of approximately 13kDa. As with many other CC chemokines, CCL2 is located on [[chromosome 17]] in humans.<ref>Mehrabian et al., Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11.2-q21.1. Genomics,1991, 9: 200-203.</ref> The cell surface receptors that bind CCL2 are [[CC chemokine receptors#CCR2|CCR2]] and [[CC chemokine receptors#CCR5|CCR5]].
The '''chemokine (C-C motif) ligand 2''' (CCL2) is also referred to as '''monocyte chemoattractant protein 1''' (MCP1) and '''small inducible cytokine A2'''. CCL2 is a small [[cytokine]] that belongs to the CC [[chemokine]] family. CCL2 recruits [[monocyte]]s, [[memory T cells]], and [[dendritic cells]] to the sites of [[inflammation]] produced by either tissue injury or [[infection]].<ref name="pmid8170963">{{cite journal | vauthors = Carr MW, Roth SJ, Luther E, Rose SS, Springer TA | title = Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 9 | pages = 3652–6 | date = Apr 1994 | pmid = 8170963 | pmc = 43639 | doi = 10.1073/pnas.91.9.3652 }}</ref><ref name="pmid8830793">{{cite journal | vauthors = Xu LL, Warren MK, Rose WL, Gong W, Wang JM | title = Human recombinant monocyte chemotactic protein and other C-C chemokines bind and induce directional migration of dendritic cells in vitro | journal = Journal of Leukocyte Biology | volume = 60 | issue = 3 | pages = 365–71 | date = Sep 1996 | pmid = 8830793 }}</ref>


==Function==
==Genomics==
CCL2 induces recruitment of [[monocytes]], [[T lymphocytes]], [[eosinophils]], and [[basophils]] and is responsible for many [[inflammation|inflammatory reactions]] to disease, and has been linked to recruitment of osteoclast precursors.


In human osteoclasts, it has been shown that CCL2 and [[RANTES]] (regulated on activation normal T cell expressed and secreted) are unregulated by [[RANKL]] (receptor activator of NFκB ligand). And that both MCP-1 and RANTES induced the formation of [[tartrate resistant acid phosphatase|TRAP-positive]], multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lacked [[cathepsin|cathepsin K]] expression and resorptive capacity. It is proposed that CCL2 and RANTES act as [[autocrine]] loop in human osteoclast [[cell differentiation|differentiation]].
In the human genome, CCL2 and many other CC chemokines are located on [[chromosome 17]] (17q11.2-q21.1).<ref name="pmid2004761">{{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 = Jan 1991 | pmid = 2004761 | doi = 10.1016/0888-7543(91)90239-B }}</ref> The gene span is 1,927 bases and the CCL2 gene resides on the Watson (plus) strand. The CCL2 gene has three [[exon]]s and two [[intron]]s. The CCL2 [[protein precursor]] contains a signal peptide of 23 [[amino acid]]s. In turn, the mature CCL2 is 76 amino acids long.<ref name="pmid2465924">{{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 = Feb 1989 | pmid = 2465924 | doi = 10.1016/0014-5793(89)80590-3 }}</ref><ref name="pmid2923622">{{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 = Feb 1989 | pmid = 2923622 | doi = 10.1016/0006-291X(89)92430-3 }}</ref> The CCL2 predicted weight is 11.025 kiloDaltons (kDa).


==References==
The gene homologous to CCL2 in the mouse is Sig-je.
{{reflist|2}}


==Further reading==
==Population genetics==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Yoshimura T, Leonard EJ |title=Human monocyte chemoattractant protein-1 (MCP-1). |journal=Adv. Exp. Med. Biol. |volume=305 |issue=  |pages= 47-56 |year= 1992 |pmid= 1661560 |doi=  }}
*{{cite journal  | author=Wahl SM, Greenwell-Wild T, Hale-Donze H, ''et al.'' |title=Permissive factors for HIV-1 infection of macrophages. |journal=J. Leukoc. Biol. |volume=68 |issue= 3 |pages= 303-10 |year= 2000 |pmid= 10985244 |doi=  }}
*{{cite journal  | author=Sell H, Eckel J |title=Monocyte chemotactic protein-1 and its role in insulin resistance. |journal=Curr. Opin. Lipidol. |volume=18 |issue= 3 |pages= 258-62 |year= 2007 |pmid= 17495598 |doi= 10.1097/MOL.0b013e3281338546 }}
}}
{{refend}}
{{Template:Chemokines}}


{{protein-stub}}
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<ref name="McDermott2005">{{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 = Aug 2005 | pmid = 16116069 | pmc =  | doi = 10.1161/CIRCULATIONAHA.105.543579 }}</ref><ref name="Bielinski2007">{{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 = Dec 2007 | pmid = 17917677 | pmc =  | doi = 10.1038/sj.gene.6364434 }}</ref>
[[category:cytokines]]


[[fr:CCL2]]
==Molecular biology==
{{WikiDoc Sources}}
 
CCL2 is a monomeric [[polypeptide]], with a [[molecular weight]] of approximately 13 kDa. CCL2 is anchored in the plasma membrane of endothelial cells by glycosaminoglycan side chains of proteoglycans. CCL2 is primarily secreted by [[monocyte]]s, [[macrophage]]s and [[dendritic cell]]s. Platelet derived growth factor is a major inducer of CCL2 gene. To become activated CCL2 protein has to be cleaved by [[metalloproteinase]] MMP-12.
 
[[CCR2]] and [[CCR4]] are two cell surface receptors that bind CCL2.<ref name="pmid17160712">{{cite journal | vauthors = Craig MJ, Loberg RD | title = CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases | journal = Cancer Metastasis Reviews | volume = 25 | issue = 4 | pages = 611–9 | date = Dec 2006 | pmid = 17160712 | pmc =  | doi = 10.1007/s10555-006-9027-x }}</ref>
 
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.<ref name="pmid8550082">{{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 = Nov 1995 | pmid = 8550082 | pmc = 1383948 }}</ref><ref name="pmid1569397">{{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 }}</ref> CCL2 augments monocyte anti-tumor activity and it is essential for formation of granulomas.
 
CCL2 can be found at the sites of tooth eruption and bone degradation. In the bone, CCL2 is expressed by mature [[osteoclast]]s and [[osteoblast]]s 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 [[tartrate resistant acid phosphatase|TRAP-positive]], multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lacked [[cathepsin|cathepsin K]] expression and resorptive capacity. It is proposed that CCL2 and RANTES act as [[autocrine]] loop in human osteoclast [[cell differentiation|differentiation]].<ref name="Kim">{{cite journal | vauthors = Kim MS, Day CJ, Morrison NA | title = MCP-1 is induced by receptor activator of nuclear factor-<nowiki/>{kappa}B 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 = Apr 2005 | pmid = 15722361 | pmc =  | doi = 10.1074/jbc.M412713200 }}</ref>
 
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.<ref name="Banisadr">{{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 = Aug 2005 | pmid = 16025454 | pmc =  | doi = 10.1002/cne.20598 }}</ref>
 
==Clinical importance==
 
CCL2 is implicated in pathogeneses of several diseases characterized by [[monocyte|monocytic]] infiltrates, such as [[psoriasis]], [[rheumatoid arthritis]] and [[atherosclerosis]].<ref name="Xia">{{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 = Mar 2009 | pmid = 19441905 | pmc =  | doi = 10.1517/13543770902755129 }}</ref>
 
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.<ref name="Lloyds">{{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 = Apr 1997 | pmid = 9104823 | pmc = 2196251 | doi = 10.1084/jem.185.7.1371 }}</ref>
 
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.<ref name="Gerard">{{cite journal | vauthors = Gerard C, Rollins BJ | title = Chemokines and disease | journal = Nature Immunology | volume = 2 | issue = 2 | pages = 108–15 | date = Feb 2001 | pmid = 11175802 | pmc =  | doi = 10.1038/84209 }}</ref> CCL2 expression in [[neuroglia|glial cells]] is increased in epilepsy,<ref name="Foresti">{{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 | year = 2009 | pmid = 20034406 | pmc = 2804573 | doi = 10.1186/1742-2094-6-40 }}</ref><ref name="Fabene">{{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 = Jul 2010 | pmid = 20542576 | pmc =  | doi = 10.1016/j.jneuroim.2010.05.016 }}</ref> brain ischemia<ref name=autogenerated1>{{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 = Feb 1995 | pmid = 7860708 | doi=10.1016/0165-5728(94)00138-e}}</ref> Alzheimer’s disease<ref name="Hickman">{{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 = Apr 2010 | pmid = 20205643 | doi = 10.2174/187152710791011982 }}</ref> [[experimental autoimmune encephalomyelitis]] (EAE),<ref name="Ransohoff">{{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 = Apr 1993 | pmid = 8472896 }}</ref> and [[traumatic brain injury]].<ref name="Semple">{{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 = Apr 2010 | pmid = 20029451 | pmc = 2949175 | doi = 10.1038/jcbfm.2009.262 }}</ref>
 
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 later plays an important role in the vascular complications of type 2 diabetes<ref name = "pmid21975431">{{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 = Jun 2012 | pmid = 21975431 | pmc =  | doi = 10.3275/7981 }}</ref>
 
CCL2 induces [[amylin]] expression through [[MAPK3|ERK1]]/[[MAPK1|ERK2]]/[[C-Jun N-terminal kinases|JNK]]-[[AP-1 (transcription factor)|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.<ref name = "pmid21589925">{{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 | year = 2011 | pmid = 21589925 | pmc = 3092759 | doi = 10.1371/journal.pone.0019559 | editor1-last = Fadini | editor1-first = Gian Paolo }}</ref>
 
[[Adipocyte]]s secrete various [[adipokine]]s 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 [[myocyte]]s. 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.<ref name = "pmid16439461">{{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 | pmc =  | doi = 10.1210/en.2005-0969 }}</ref>
 
Incubation of HL-1 [[cardiomyocyte]]s and human myocytes with oxidized-LDL induced the expression of [[brain natriuretic peptide|BNP]] and CCL2 genes, while native LDL (N-LDL) had no effect.<ref name = "pmid21900689">{{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 = Jan 2012 | pmid = 21900689 | pmc =  | doi = 10.1152/ajpcell.00116.2011 }}</ref>
 
Treatment with melatonin in old mice with age related liver inflammation decreased the mRNA expression of [[Tumor necrosis factor-alpha|TNF-α]], [[IL1B|IL-1β]], HO ([[HMOX1|HO-1]] and [[HMOX2|HO-2]]), [[nitric oxide synthase|iNOS]], CCL2, [[NFKB1|NF-κB1]], [[NFKB2|NF-κB2]] and NKAP in old male mice. The protein expression of [[Tumor necrosis factor-alpha|TNF-α]], [[IL1B|IL-1β]] was also decreased and [[interleukin 10|IL-10]] increased with melatonin treatment. Exogenous administration of [[melatonin]] was able to reduce inflammation.<ref name = "pmid20817086">{{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 = Dec 2010 | pmid = 20817086 | pmc =  | doi = 10.1016/j.exger.2010.08.016 }}</ref>
 
== References ==
{{Reflist|33em}}
 
==External links==
* {{UCSC gene info|CCL2}}
 
== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Yoshimura T, Leonard EJ | title = Human monocyte chemoattractant protein-1 (MCP-1) | journal = Advances in Experimental Medicine and Biology | volume = 305 | pages = 47–56 | year = 1991 | pmid = 1661560 | doi = 10.1007/978-1-4684-6009-4_6 }}
* {{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 = Sep 2000 | pmid = 10985244 }}
* {{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 = Jun 2007 | pmid = 17495598 | pmc =  | doi = 10.1097/MOL.0b013e3281338546 }}
{{Refend}}
 
 
{{PDB Gallery|geneid=6347}}
{{Chemokines}}
{{Chemokine receptor modulators}}
 
{{DEFAULTSORT:Ccl2}}
 
[[Category:Cytokines]]

Revision as of 13:11, 11 April 2017

For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.

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Orthologs
SpeciesHumanMouse
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Ensembl

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RefSeq (mRNA)

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RefSeq (protein)

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View/Edit Human

The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL2 is a small cytokine that belongs to the CC chemokine family. CCL2 recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection.[1][2]

Genomics

In the human genome, CCL2 and many other CC chemokines are located on chromosome 17 (17q11.2-q21.1).[3] 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.[4][5] The CCL2 predicted weight is 11.025 kiloDaltons (kDa).

The gene homologous to CCL2 in the mouse is Sig-je.

Population genetics

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[6][7]

Molecular biology

CCL2 is a monomeric polypeptide, with a molecular weight of approximately 13 kDa. 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. To become activated CCL2 protein has to be cleaved by metalloproteinase MMP-12.

CCR2 and CCR4 are two cell surface receptors that bind CCL2.[8]

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.[9][10] CCL2 augments monocyte anti-tumor activity and it is essential for formation of granulomas.

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.[11]

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.[12]

Clinical importance

CCL2 is implicated in pathogeneses of several diseases characterized by monocytic infiltrates, such as psoriasis, rheumatoid arthritis and atherosclerosis.[13]

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.[14]

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.[15] CCL2 expression in glial cells is increased in epilepsy,[16][17] brain ischemia[18] Alzheimer’s disease[19] experimental autoimmune encephalomyelitis (EAE),[20] and traumatic brain injury.[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 later plays an important role in the vascular complications of type 2 diabetes[22]

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.[23]

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.[24]

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.[25]

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.[26]

References

  1. ↑ Carr MW, Roth SJ, Luther E, Rose SS, Springer TA (Apr 1994). "Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant". Proceedings of the National Academy of Sciences of the United States of America. 91 (9): 3652–6. doi:10.1073/pnas.91.9.3652. PMC 43639. PMID 8170963.
  2. ↑ Xu LL, Warren MK, Rose WL, Gong W, Wang JM (Sep 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. PMID 8830793.
  3. ↑ Mehrabian M, Sparkes RS, Mohandas T, Fogelman AM, Lusis AJ (Jan 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. PMID 2004761.
  4. ↑ Yoshimura T, Yuhki N, Moore SK, Appella E, Lerman MI, Leonard EJ (Feb 1989). "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". FEBS Letters. 244 (2): 487–93. doi:10.1016/0014-5793(89)80590-3. PMID 2465924.
  5. ↑ Furutani Y, Nomura H, Notake M, Oyamada Y, Fukui T, Yamada M, Larsen CG, Oppenheim JJ, Matsushima K (Feb 1989). "Cloning and sequencing of the cDNA for human monocyte chemotactic and activating factor (MCAF)". Biochemical and Biophysical Research Communications. 159 (1): 249–55. doi:10.1016/0006-291X(89)92430-3. PMID 2923622.
  6. ↑ 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 (Aug 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. PMID 16116069.
  7. ↑ Bielinski SJ, Pankow JS, Miller MB, Hopkins PN, Eckfeldt JH, Hixson J, Liu Y, Register T, Myers RH, Arnett DK (Dec 2007). "Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI family heart study follow-up examination". Genes and Immunity. 8 (8): 684–90. doi:10.1038/sj.gene.6364434. PMID 17917677.
  8. ↑ Craig MJ, Loberg RD (Dec 2006). "CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases". Cancer Metastasis Reviews. 25 (4): 611–9. doi:10.1007/s10555-006-9027-x. PMID 17160712.
  9. ↑ Conti P, Boucher W, Letourneau R, Feliciani C, Reale M, Barbacane RC, Vlagopoulos P, Bruneau G, Thibault J, Theoharides TC (Nov 1995). "Monocyte chemotactic protein-1 provokes mast cell aggregation and [3H]5HT release". Immunology. 86 (3): 434–40. PMC 1383948. PMID 8550082.
  10. ↑ Bischoff SC, Krieger M, Brunner T, Dahinden CA (May 1992). "Monocyte chemotactic protein 1 is a potent activator of human basophils". The Journal of Experimental Medicine. 175 (5): 1271–5. doi:10.1084/jem.175.5.1271. PMC 2119199. PMID 1569397.
  11. ↑ Kim MS, Day CJ, Morrison NA (Apr 2005). "MCP-1 is induced by receptor activator of nuclear factor-{kappa}B ligand, promotes human osteoclast fusion, and rescues granulocyte macrophage colony-stimulating factor suppression of osteoclast formation". The Journal of Biological Chemistry. 280 (16): 16163–9. doi:10.1074/jbc.M412713200. PMID 15722361.
  12. ↑ Banisadr G, Gosselin RD, Mechighel P, Kitabgi P, Rostène W, Parsadaniantz SM (Aug 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. PMID 16025454.
  13. ↑ Xia M, Sui Z (Mar 2009). "Recent developments in CCR2 antagonists". Expert Opinion on Therapeutic Patents. 19 (3): 295–303. doi:10.1517/13543770902755129. PMID 19441905.
  14. ↑ Lloyd CM, Minto AW, Dorf ME, Proudfoot A, Wells TN, Salant DJ, Gutierrez-Ramos JC (Apr 1997). "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". The Journal of Experimental Medicine. 185 (7): 1371–80. doi:10.1084/jem.185.7.1371. PMC 2196251. PMID 9104823.
  15. ↑ Gerard C, Rollins BJ (Feb 2001). "Chemokines and disease". Nature Immunology. 2 (2): 108–15. doi:10.1038/84209. PMID 11175802.
  16. ↑ Foresti ML, Arisi GM, Katki K, Montañez A, Sanchez RM, Shapiro LA (2009). "Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus". Journal of Neuroinflammation. 6: 40. doi:10.1186/1742-2094-6-40. PMC 2804573. PMID 20034406.
  17. ↑ Fabene PF, Bramanti P, Constantin G (Jul 2010). "The emerging role for chemokines in epilepsy". Journal of Neuroimmunology. 224 (1–2): 22–7. doi:10.1016/j.jneuroim.2010.05.016. PMID 20542576.
  18. ↑ Kim JS, Gautam SC, Chopp M, Zaloga C, Jones ML, Ward PA, Welch KM (Feb 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. PMID 7860708.
  19. ↑ Hickman SE, El Khoury J (Apr 2010). "Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease". CNS & Neurological Disorders Drug Targets. 9 (2): 168–73. doi:10.2174/187152710791011982. PMID 20205643.
  20. ↑ Ransohoff RM, Hamilton TA, Tani M, Stoler MH, Shick HE, Major JA, Estes ML, Thomas DM, Tuohy VK (Apr 1993). "Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis". FASEB Journal. 7 (6): 592–600. PMID 8472896.
  21. ↑ Semple BD, Bye N, Rancan M, Ziebell JM, Morganti-Kossmann MC (Apr 2010). "Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice". Journal of Cerebral Blood Flow and Metabolism. 30 (4): 769–82. doi:10.1038/jcbfm.2009.262. PMC 2949175. PMID 20029451.
  22. ↑ Liu ZH, Chen LL, Deng XL, Song HJ, Liao YF, Zeng TS, Zheng J, Li HQ (Jun 2012). "Methylation status of CpG sites in the MCP-1 promoter is correlated to serum MCP-1 in Type 2 diabetes". Journal of Endocrinological Investigation. 35 (6): 585–9. doi:10.3275/7981. PMID 21975431.
  23. ↑ Cai K, Qi D, Hou X, Wang O, Chen J, Deng B, Qian L, Liu X, Le Y (2011). Fadini GP, ed. "MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2". PLOS ONE. 6 (5): e19559. doi:10.1371/journal.pone.0019559. PMC 3092759. PMID 21589925.
  24. ↑ Sell H, Dietze-Schroeder D, Kaiser U, Eckel J (May 2006). "Monocyte chemotactic protein-1 is a potential player in the negative cross-talk between adipose tissue and skeletal muscle". Endocrinology. 147 (5): 2458–67. doi:10.1210/en.2005-0969. PMID 16439461.
  25. ↑ Chandrakala AN, Sukul D, Selvarajan K, Sai-Sudhakar C, Sun B, Parthasarathy S (Jan 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. PMID 21900689.
  26. ↑ Cuesta S, Kireev R, Forman K, García C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA (Dec 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. PMID 20817086.

External links

Further reading

  • Yoshimura T, Leonard EJ (1991). "Human monocyte chemoattractant protein-1 (MCP-1)". Advances in Experimental Medicine and Biology. 305: 47–56. doi:10.1007/978-1-4684-6009-4_6. PMID 1661560.
  • Wahl SM, Greenwell-Wild T, Hale-Donze H, Moutsopoulos N, Orenstein JM (Sep 2000). "Permissive factors for HIV-1 infection of macrophages". Journal of Leukocyte Biology. 68 (3): 303–10. PMID 10985244.
  • Sell H, Eckel J (Jun 2007). "Monocyte chemotactic protein-1 and its role in insulin resistance". Current Opinion in Lipidology. 18 (3): 258–62. doi:10.1097/MOL.0b013e3281338546. PMID 17495598.


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