同: MCP-1

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/04/10 12:44:11」(JST)

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

The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemotactic 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 releases 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

^ Carr, M. W.; Roth, S. J.; Luther, E.; Rose, S. S.; Springer, T. A. (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): 3652–3656. doi:10.1073/pnas.91.9.3652. PMC 43639. PMID 8170963. edit
^ Xu, L. L.; Warren, M. K.; Rose, W. L.; Gong, W.; Wang, J. M. (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): 365–371. PMID 8830793. edit
^ Mehrabian, M.; Sparkes, R. S.; Mohandas, T.; Fogelman, A. M.; Lusis, A. J. (1991). "Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11.2-q21.1". Genomics 9 (1): 200–203. doi:10.1016/0888-7543(91)90239-B. PMID 2004761. edit
^ Yoshimura, T.; Yuhki, N.; Moore, S. K.; Appella, E.; Lerman, M. I.; Leonard, E. J. (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): 487–493. doi:10.1016/0014-5793(89)80590-3. PMID 2465924. edit
^ Furutani, Y.; Nomura, H.; Notake, M.; Oyamada, Y.; Fukui, T.; Yamada, M.; Larsen, C. G.; Oppenheim, J. J.; Matsushima, K. (1989). "Cloning and sequencing of the cDNA for human monocyte chemotactic and activating factor (MCAF)". Biochemical and Biophysical Research Communications 159 (1): 249–255. doi:10.1016/0006-291X(89)92430-3. PMID 2923622. edit
^ McDermott, D. H.; Yang, Q.; Kathiresan, S.; Cupples, L. A.; Massaro, J. M.; Keaney Jr, J. F.; Larson, M. G.; Vasan, R. S.; Hirschhorn, J. N.; O'Donnell, C. J.; Murphy, P. M.; Benjamin, E. J. (2005). "CCL2 Polymorphisms Are Associated with Serum Monocyte Chemoattractant Protein-1 Levels and Myocardial Infarction in the Framingham Heart Study". Circulation 112 (8): 1113–1120. doi:10.1161/CIRCULATIONAHA.105.543579. PMID 16116069. edit
^ Bielinski, S. J.; Pankow, J. S.; Miller, M. B.; Hopkins, P. N.; Eckfeldt, J. H.; Hixson, J.; Liu, Y.; Register, T.; Myers, R. H.; Arnett, D. K. (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): 684–690. doi:10.1038/sj.gene.6364434. PMID 17917677. edit
^ Craig, M. J.; Loberg, R. D. (2006). "CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases". Cancer and Metastasis Reviews 25 (4): 611–619. doi:10.1007/s10555-006-9027-x. PMID 17160712. edit
^ Conti, P.; Boucher, W.; Letourneau, R.; Feliciani, C.; Reale, M.; Barbacane, R. C.; Vlagopoulos, P.; Bruneau, G.; Thibault, J.; Theoharides, T. C. (1995). "Monocyte chemotactic protein-1 provokes mast cell aggregation and 3H5HT release". Immunology 86 (3): 434–440. PMC 1383948. PMID 8550082. edit
^ Bischoff, S. C.; Krieger, M.; Brunner, T.; Dahinden, C. A. (1992). "Monocyte chemotactic protein 1 is a potent activator of human basophils". The Journal of experimental medicine 175 (5): 1271–1275. doi:10.1084/jem.175.5.1271. PMC 2119199. PMID 1569397. edit
^ Kim, M. S.; Day, C. J.; Morrison, N. A. (2005). "MCP-1 is Induced by Receptor Activator of Nuclear Factor- B Ligand, Promotes Human Osteoclast Fusion, and Rescues Granulocyte Macrophage Colony-stimulating Factor Suppression of Osteoclast Formation". Journal of Biological Chemistry 280 (16): 16163–16169. doi:10.1074/jbc.M412713200. PMID 15722361. edit
^ Banisadr, G.; Gosselin, R. D.; Mechighel, P.; Kitabgi, P.; Rostène, W.; Parsadaniantz, S. P. M. L. (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): 275–292. doi:10.1002/cne.20598. PMID 16025454. edit
^ Xia, M.; Sui, Z. (2009). "Recent developments in CCR2 antagonists". Expert Opinion on Therapeutic Patents 19 (3): 295–303. doi:10.1517/13543770902755129. PMID 19441905. edit
^ Lloyd, C. M.; Minto, A. W.; Dorf, M. E.; Proudfoot, A.; Wells, T. N.; Salant, D. J.; Gutierrez-Ramos, J. C. (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): 1371–1380. doi:10.1084/jem.185.7.1371. PMC 2196251. PMID 9104823. edit
^ Gerard, C.; Rollins, B. J. (2001). "Chemokines and disease". Nature Immunology 2 (2): 108–115. doi:10.1038/84209. PMID 11175802. edit
^ Foresti, M. L.; Arisi, G. M.; Katki, K.; Montañez, A.; Sanchez, R. M.; Shapiro, L. A. (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. edit
^ Fabene, P. F.; Bramanti, P.; Constantin, G. (2010). "The emerging role for chemokines in epilepsy". Journal of Neuroimmunology 224 (1–2): 22–27. doi:10.1016/j.jneuroim.2010.05.016. PMID 20542576. edit
^ Kim, J. S.; Gautam, S. C.; Chopp, M.; Zaloga, C.; Jones, M. L.; Ward, P. A.; Welch, K. M. (1995). "Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat". Journal of neuroimmunology 56 (2): 127–134. PMID 7860708. edit
^ Hickman, S. E.; El Khoury, J. (2010). "Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease". CNS & neurological disorders drug targets 9 (2): 168–173. doi:10.2174/187152710791011982. PMID 20205643. edit
^ Ransohoff, R. M.; Hamilton, T. A.; Tani, M.; Stoler, M. H.; Shick, H. E.; Major, J. A.; Estes, M. L.; Thomas, D. M.; Tuohy, V. K. (1993). "Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis". The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 (6): 592–600. PMID 8472896. edit
^ Semple, B. D.; Bye, N.; Rancan, M.; Ziebell, J. M.; Morganti-Kossmann, M. C. (2009). "Role of CCL2 (MCP-1) in traumatic brain injury (TBI): Evidence from severe TBI patients and CCL2−/− mice". Journal of Cerebral Blood Flow & Metabolism 30 (4): 769–782. doi:10.1038/jcbfm.2009.262. PMC 2949175. PMID 20029451. edit
^ Liu, Z. H.; Chen, L. L.; Deng, X. L.; Song, H. J.; Liao, Y. F.; Zeng, T. S.; Zheng, J.; Li, H. Q. (2011). "Methylation Status of CpG Sites in the MCP-1 Promoter is Correlated to Serum MCP-1 in type 2 Diabetes". Journal of endocrinological investigation. doi:10.3275/7981. PMID 21975431. edit
^ Cai, K.; Qi, D.; Hou, X.; Wang, O.; Chen, J.; Deng, B.; Qian, L.; Liu, X.; Le, Y. (2011). Fadini, Gian Paolo, 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. edit
^ Sell, H.; Dietze-Schroeder, D.; Kaiser, U.; Eckel, J. (2006). "Monocyte Chemotactic Protein-1 is a Potential Player in the Negative Cross-Talk between Adipose Tissue and Skeletal Muscle". Endocrinology 147 (5): 2458–2467. doi:10.1210/en.2005-0969. PMID 16439461. edit
^ Chandrakala, A. N.; Sukul, D.; Selvarajan, K.; Sai-Sudhakar, C.; Sun, B.; Parthasarathy, S. (2011). "Induction of Brain Natriuretic Peptide and Monocyte Chemotactic Protein1 Gene Expressions by Oxidized Lowdensity Lipoprotein-Relevance to Ischemic Heart Failure". AJP: Cell Physiology 302 (1): C165–77. doi:10.1152/ajpcell.00116.2011. PMID 21900689. edit
^ Cuesta, S.; Kireev, R.; Forman, K.; García, C.; Escames, G.; Ariznavarreta, C.; Vara, E.; Tresguerres, J. S. A. F. (2010). "Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8)". Experimental Gerontology 45 (12): 950–956. doi:10.1016/j.exger.2010.08.016. PMID 20817086. edit

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English Journal

CCL2 affects β-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer's disease.

Kiyota T, Gendelman HE, Weir RA, Higgins EE, Zhang G, Jain M.SourceCenter for Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: tkiyota@unmc.edu.
Neurobiology of aging.Neurobiol Aging.2013 Apr;34(4):1060-8. doi: 10.1016/j.neurobiolaging.2012.08.009. Epub 2012 Oct 4.
Neuroinflammation affects the pathobiology of Alzheimer's disease (AD). Notably, β-amyloid (Aβ) deposition induces microglial activation and the subsequent production of proinflammatory neurotoxic factors. In maintaining brain homeostasis, microglial plasticity also enables phenotypic transition b
PMID 23040664

Modulation of chemokine and chemokine receptor expression following infection of porcine macrophages with African swine fever virus.

Fishbourne E, Abrams CC, Takamatsu HH, Dixon LK.SourceThe Pirbright Institute, Ash Road, Pirbright, Woking, Surrey GU24 0NF, UK.
Veterinary microbiology.Vet Microbiol.2013 Mar 23;162(2-4):937-43. doi: 10.1016/j.vetmic.2012.11.027. Epub 2012 Nov 29.
African swine fever virus (ASFV) is the only member of the Asfarviridae, a large DNA virus family which replicates predominantly in the cytoplasm. Most isolates cause a fatal haemorrhagic disease in domestic pigs, although some low virulence isolates cause little or no mortality. The modulation of c
PMID 23265239

Japanese Journal

Methylmercury induces CCL2 expression through activation of NF-κB in human 1321N1 astrocytes

Kim Min-Seok,Takahashi Tsutomu,Lee Jin-Yong [他]
The Journal of toxicological sciences 37(6), 1275-1278, 2012-12
NAID 40019524064

Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirpα + dendritic cells: A murine model

Baba Tomohisa,Badr M.E.S.,Tomaru Utano,Ishizu Akihiro,Mukaida Naofumi
PLoS ONE 7(7), e41154, 2012-07-16
… Furthermore, CCR2 expression by thymic Sirpα + cDCs and abundant expression of its ligands, particularly, CCL2 by tumor-bearing mice prompted us to examine the function of thymic Sirpα + cDCs in tumor-bearing mice. … Interestingly, tumor-bearing mice deposited CCL2 inside IVRs in the thymus. …
NAID 120004419373

Related Pictures

★リンクテーブル★

リンク元	「MCP-1」
拡張検索	「chemokine CCL2」
関連記事	「CC」「CCL」

「MCP-1」

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
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; • cytoplasm; • neuronal cell body;
Biological process	• MAPK cascade; • angiogenesis; • response to hypoxia; • positive regulation of endothelial cell proliferation; • monocyte chemotaxis; • protein phosphorylation; • cellular calcium ion homeostasis; • chemotaxis; • inflammatory response; • humoral immune response; • activation of signaling protein activity involved in unfolded protein 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 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; • response to vitamin B3; • negative regulation of glial cell apoptotic process; • helper T cell extravasation; • response to drug; • response to amino acid; • protein kinase B signaling; • negative regulation of neuron apoptotic process; • 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; • macrophage chemotaxis; • lymphocyte chemotaxis; • positive regulation of synaptic transmission; • positive regulation of T cell activation; • response to glucocorticoid; • positive regulation of nitric-oxide synthase biosynthetic process; • maternal process involved in parturition; • chemokine-mediated signaling pathway; • cellular response to lipopolysaccharide; • cellular response to interferon-gamma; • cellular response to interleukin-1; • cellular response to tumor necrosis factor; • cellular response to organic cyclic compound; • positive regulation of immune complex clearance by monocytes and macrophages; • positive regulation of calcium ion import; • positive regulation of apoptotic cell clearance; • negative regulation of natural killer cell chemotaxis;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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