CCL2

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

Chemokine (C-C motif) ligand 2
PDB rendering based on 1dok.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1DOK​, 1DOL​, 1DOM​, 1DON​, 1MCA​, 1ML0​, 2BDN​, 2NZ1​, 3IFD​, 4DN4​, 4R8I​
Identifiers
Symbols	CCL2 ; GDCF-2; HC11; HSMCR30; MCAF; MCP-1; MCP1; SCYA2; SMC-CF
External IDs	OMIM: 158105 MGI: 98259 HomoloGene: 2245 ChEMBL: 1649052 GeneCards: CCL2 Gene
Gene ontology Molecular function • protein kinase activity • receptor binding • chemokine activity • heparin binding • CCR2 chemokine receptor binding Cellular component • extracellular region • extracellular space • rough endoplasmic reticulum • endocytic vesicle • dendrite • perikaryon • axon terminus • C-fiber • synapse • perinuclear region of cytoplasm Biological process • MAPK cascade • angiogenesis • response to hypoxia • positive regulation of leukocyte mediated cytotoxicity • positive regulation of endothelial cell proliferation • leukocyte migration involved in inflammatory response • monocyte chemotaxis • positive regulation of cellular extravasation • protein phosphorylation • cellular calcium ion homeostasis • chemotaxis • inflammatory response • humoral immune response • cytoskeleton organization • cell adhesion • signal transduction • cell surface receptor signaling pathway • transforming growth factor beta receptor signaling pathway • G-protein coupled receptor signaling pathway • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • JAK-STAT cascade • aging • regulation of cell shape • response to heat • response to wounding • response to mechanical stimulus • response to bacterium • organ morphogenesis • response to gamma radiation • regulation of vascular endothelial growth factor production • positive regulation of macrophage chemotaxis • response to activity • negative regulation of angiogenesis • viral genome replication • cytokine-mediated signaling pathway • cellular homeostasis • neutrophil chemotaxis • endoplasmic reticulum unfolded protein response • organ regeneration • lipopolysaccharide-mediated signaling pathway • response to progesterone • positive regulation of tumor necrosis factor production • cellular response to insulin stimulus • positive regulation of collagen biosynthetic process • response to vitamin B3 • negative regulation of glial cell apoptotic process • helper T cell extravasation • cellular response to drug • cellular response to macrophage colony-stimulating factor stimulus • cellular response to platelet-derived growth factor stimulus • PERK-mediated unfolded protein response • response to amino acid • protein kinase B signaling • negative regulation of neuron apoptotic process • positive regulation of GTPase activity • astrocyte cell migration • cellular protein metabolic process • cellular response to fibroblast growth factor stimulus • response to ethanol • response to antibiotic • vascular endothelial growth factor receptor signaling pathway • eosinophil chemotaxis • macrophage chemotaxis • lymphocyte chemotaxis • positive regulation of synaptic transmission • positive regulation of T cell activation • positive regulation of nitric-oxide synthase biosynthetic process • maternal process involved in female pregnancy • maternal process involved in parturition • chemokine-mediated signaling pathway • positive regulation of ERK1 and ERK2 cascade • cellular response to lipopolysaccharide • cellular response to retinoic acid • cellular response to ATP • cellular response to interferon-gamma • cellular response to interleukin-1 • cellular response to interleukin-6 • cellular response to tumor necrosis factor • cellular response to high density lipoprotein particle stimulus • cellular response to organic cyclic compound • cellular response to dexamethasone stimulus • positive regulation of monocyte chemotaxis • positive regulation of immune complex clearance by monocytes and macrophages • positive regulation of calcium ion import • positive regulation of protein targeting to membrane • positive regulation of apoptotic cell clearance • negative regulation of natural killer cell chemotaxis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6347	20293
Ensembl	ENSG00000108691	ENSMUSG00000035352
UniProt	P13500	Q62401
RefSeq (mRNA)	NM_002982	NM_011331
RefSeq (protein)	NP_002973	NP_035461
Location (UCSC)	Chr 17: 34.26 – 34.26 Mb	Chr 11: 82.1 – 82.1 Mb
PubMed search

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.

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.