Jump to content

CCL2

From Wikipedia, the free encyclopedia

CCL2
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesCCL2,GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1, SCYA2, SMC-CF, C-C motif chemokine ligand 2
External IDsOMIM:158105;MGI:108224;HomoloGene:2245;GeneCards:CCL2;OMA:CCL2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002982

NM_011331

RefSeq (protein)

NP_002973

NP_035461

Location (UCSC)Chr 17: 34.26 – 34.26 MbChr 11: 81.99 – 81.99 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Thechemokine (C-C motif) ligand 2(CCL2) is also referred to asmonocyte chemoattractant protein 1(MCP1) andsmall inducible cytokine A2.CCL2 is a smallcytokinethat belongs to theCC chemokinefamily. CCL2 tightly regulates cellular mechanics[5]and thereby recruitsmonocytes,memory T cells,anddendritic cellsto the sites ofinflammationproduced by either tissue injury orinfection.[6][7]

Genomics

[edit]

In thehuman genome,CCL2 and many other CC chemokines are located onchromosome 17(17q11.2-q21.1).[8]The gene span is 1,927 bases and the CCL2 gene resides on the Watson (plus) strand. The CCL2 gene has threeexonsand twointrons.The CCL2protein precursorcontains a signal peptide of 23amino acids.In turn, the mature CCL2 is 76 amino acids long.[9][10]The CCL2 predicted weight is 11.025 kilodaltons (kDa).

Population genetics

[edit]

In humans, the levels of CCL2 can vary considerably. In the white people of European descent, the multivariable-adjusted heritability of CCL2 concentrations is as much as 0.37 in the blood plasma and 0.44 - in the serum.[11][12]

Molecular biology

[edit]

CCL2 is a monomericpolypeptide,with amolecular weightof approximately 13-15 kDa depending on levels ofglycosylation.[13]CCL2 is anchored in the plasma membrane of endothelial cells byglycosaminoglycanside chains of proteoglycans. CCL2 is primarily secreted bymonocytes,macrophagesanddendritic cells.Platelet derived growth factor is a major inducer of CCL2 gene.

CCR2andCCR4are two cell surface receptors that bind CCL2.[14]

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.[15][16]CCL2 augments monocyte anti-tumor activity and it is essential for formation of granulomas. CCL2 protein become aCCR2antagonist when it is cleaved bymetalloproteinaseMMP-12.[17]

CCL2 can be found at the sites of tooth eruption and bone degradation. In the bone, CCL2 is expressed by matureosteoclastsandosteoblastsand it is under control of nuclear factor κB (NFκB). In the human osteoclasts, CCL2 andRANTES(regulated on activation normal T cell expressed and secreted). Both MCP-1 and RANTES induce formation ofTRAP-positive,multinuclear cells from M-CSF-treated monocytes in the absence of RANKL, but produced osteoclasts that lackedcathepsin Kexpression and resorptive capacity. It is proposed that CCL2 and RANTES act asautocrineloop in human osteoclastdifferentiation.[18]

The CCL2 chemokine is also expressed by neurons, astrocytes and microglia. The expression of CCL2 in neurons is mainly found in the cerebral cortex, globus pallidus, hippocampus, paraventricular and supraoptic hypothalamic nuclei, lateral hypothalamus, substantia nigra, facial nuclei, motor and spinal trigeminal nuclei, gigantocellular reticular nucleus and in Purkinje cells in the cerebellum.[19]

Clinical importance

[edit]

CCL2 is implicated in pathogeneses of several diseases characterized bymonocyticinfiltrates, such aspsoriasis,rheumatoid arthritisandatherosclerosis.[20]

Administration of anti-CCL2 antibodies in a model ofglomerulonephritisreduces infiltration of macrophages and T cells, reduces crescent formation, as well as scarring and renal impairment.[21]

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.[22]CCL2 expression inglial cellsis increased in epilepsy,[23][24]brain ischemia[25]Alzheimer's disease[26]experimental autoimmune encephalomyelitis(EAE),[27]andtraumatic brain injury.[28]

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.[29]

CCL2 inducesamylinexpression throughERK1/ERK2/JNK-AP1andNF-κBrelated signaling pathways independent ofCCR2.Amylin upregulation by CCL2 contributes to the elevation of the plasma amylin and insulin resistance in obesity.[30]

Adipocytessecrete variousadipokinesthat may be involved in the negative cross-talk between adipose tissue and skeletal muscle. CCL2 impairs insulin signaling in skeletal muscle cells via ERK1/2 activation at doses similar to its physiological plasma concentrations (200 pg/mL), but does not involve activation of the NF-κB pathway. CCL2 significantly reduced insulin-stimulated glucose uptake inmyocytes.CCL2 may represent a molecular link in the negative cross-talk between adipose tissue and skeletal muscle assigning a completely novel important role to CCL2 besides inflammation.[31]

Incubation of HL-1cardiomyocytesand human myocytes with oxidized-LDL induced the expression ofBNPand CCL2 genes, while native LDL (N-LDL) had no effect.[32]

Treatment with melatonin in old mice with age related liver inflammation decreased the mRNA expression ofTNF-α,IL-1β,HO (HO-1andHO-2),iNOS,CCL2,NF-κB1,NF-κB2and NKAP in old male mice. The protein expression ofTNF-α,IL-1βwas also decreased andIL-10increased with melatonin treatment. Exogenous administration ofmelatoninwas able to reduce inflammation.[33]

References

[edit]
  1. ^abcGRCh38: Ensembl release 89: ENSG00000108691Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000035352Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Evers TM, Sheikhhassani V, Haks MC, Storm C, Ottenhoff TH, Mashaghi A (January 2022)."Single-cell analysis reveals chemokine-mediated differential regulation of monocyte mechanics".iScience.25(1): 103555.Bibcode:2022iSci...25j3555E.doi:10.1016/j.isci.2021.103555.PMC8693412.PMID34988399.
  6. ^Carr MW, Roth SJ, Luther E, Rose SS, Springer TA (April 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.Bibcode:1994PNAS...91.3652C.doi:10.1073/pnas.91.9.3652.PMC43639.PMID8170963.
  7. ^Xu LL, Warren MK, Rose WL, Gong W, Wang JM (September 1996). "Human recombinant monocyte chemotactic protein and other C-C chemokines bind and induce directional migration of dendritic cells in vitro".Journal of Leukocyte Biology.60(3): 365–71.doi:10.1002/jlb.60.3.365.PMID8830793.S2CID24481789.
  8. ^Mehrabian M, Sparkes RS, Mohandas T, Fogelman AM, Lusis AJ (January 1991). "Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11.2-q21.1".Genomics.9(1): 200–3.doi:10.1016/0888-7543(91)90239-B.PMID2004761.
  9. ^Yoshimura T, Yuhki N, Moore SK, Appella E, Lerman MI, Leonard EJ (February 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.Bibcode:1989FEBSL.244..487Y.doi:10.1016/0014-5793(89)80590-3.PMID2465924.S2CID7097272.
  10. ^Furutani Y, Nomura H, Notake M, Oyamada Y, Fukui T, Yamada M, Larsen CG, Oppenheim JJ, Matsushima K (February 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.PMID2923622.
  11. ^McDermott DH, Yang Q, Kathiresan S, Cupples LA, Massaro JM, Keaney JF, Larson MG, Vasan RS, Hirschhorn JN, O'Donnell CJ, Murphy PM, Benjamin EJ (August 2005). "CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study".Circulation.112(8): 1113–20.doi:10.1161/CIRCULATIONAHA.105.543579.PMID16116069.S2CID12320863.
  12. ^Bielinski SJ, Pankow JS, Miller MB, Hopkins PN, Eckfeldt JH, Hixson J, Liu Y, Register T, Myers RH, Arnett DK (December 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.PMID17917677.S2CID8242432.
  13. ^Yoshimura T (April 2018)."The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally?".Cellular & Molecular Immunology.15(4): 335–345.doi:10.1038/cmi.2017.135.PMC6052833.PMID29375123.
  14. ^Craig MJ, Loberg RD (December 2006). "CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases".Cancer and Metastasis Reviews.25(4): 611–9.doi:10.1007/s10555-006-9027-x.PMID17160712.S2CID24366011.
  15. ^Conti P, Boucher W, Letourneau R, Feliciani C, Reale M, Barbacane RC, Vlagopoulos P, Bruneau G, Thibault J, Theoharides TC (November 1995)."Monocyte chemotactic protein-1 provokes mast cell aggregation and [3H]5HT release".Immunology.86(3): 434–40.PMC1383948.PMID8550082.
  16. ^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.PMC2119199.PMID1569397.
  17. ^Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM (October 2008)."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".Blood.112(8): 3455–64.doi:10.1182/blood-2007-12-129080.PMID18660381.S2CID25944573.
  18. ^Kim MS, Day CJ, Morrison NA (April 2005)."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".The Journal of Biological Chemistry.280(16): 16163–9.doi:10.1074/jbc.M412713200.PMID15722361.S2CID22756184.
  19. ^Banisadr G, Gosselin RD, Mechighel P, Kitabgi P, Rostène W, Parsadaniantz SM (August 2005). "Highly regionalized neuronal expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) in rat brain: evidence for its colocalization with neurotransmitters and neuropeptides".The Journal of Comparative Neurology.489(3): 275–92.doi:10.1002/cne.20598.PMID16025454.S2CID22254007.
  20. ^Xia M, Sui Z (March 2009). "Recent developments in CCR2 antagonists".Expert Opinion on Therapeutic Patents.19(3): 295–303.doi:10.1517/13543770902755129.PMID19441905.S2CID45028620.
  21. ^Lloyd CM, Minto AW, Dorf ME, Proudfoot A, Wells TN, Salant DJ, Gutierrez-Ramos JC (April 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.PMC2196251.PMID9104823.
  22. ^Gerard C, Rollins BJ (February 2001). "Chemokines and disease".Nature Immunology.2(2): 108–15.doi:10.1038/84209.PMID11175802.S2CID28336866.
  23. ^Foresti ML, Arisi GM, Katki K, Montañez A, Sanchez RM, Shapiro LA (December 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.PMC2804573.PMID20034406.
  24. ^Fabene PF, Bramanti P, Constantin G (July 2010). "The emerging role for chemokines in epilepsy".Journal of Neuroimmunology.224(1–2): 22–7.doi:10.1016/j.jneuroim.2010.05.016.PMID20542576.S2CID5121343.
  25. ^Kim JS, Gautam SC, Chopp M, Zaloga C, Jones ML, Ward PA, Welch KM (February 1995). "Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat".Journal of Neuroimmunology.56(2): 127–34.doi:10.1016/0165-5728(94)00138-e.PMID7860708.S2CID45538922.
  26. ^Hickman SE, El Khoury J (April 2010)."Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease".CNS & Neurological Disorders Drug Targets.9(2): 168–73.doi:10.2174/187152710791011982.PMC3684802.PMID20205643.
  27. ^Ransohoff RM, Hamilton TA, Tani M, Stoler MH, Shick HE, Major JA, Estes ML, Thomas DM, Tuohy VK (April 1993)."Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis".FASEB Journal.7(6): 592–600.doi:10.1096/fasebj.7.6.8472896.PMID8472896.S2CID13552110.
  28. ^Semple BD, Bye N, Rancan M, Ziebell JM, Morganti-Kossmann MC (April 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.PMC2949175.PMID20029451.
  29. ^Liu ZH, Chen LL, Deng XL, Song HJ, Liao YF, Zeng TS, Zheng J, Li HQ (June 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.PMID21975431.S2CID14613351.
  30. ^Cai K, Qi D, Hou X, Wang O, Chen J, Deng B, Qian L, Liu X, Le Y (May 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.Bibcode:2011PLoSO...619559C.doi:10.1371/journal.pone.0019559.PMC3092759.PMID21589925.
  31. ^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.PMID16439461.
  32. ^Chandrakala AN, Sukul D, Selvarajan K, Sai-Sudhakar C, Sun B, Parthasarathy S (January 2012). "Induction of brain natriuretic peptide and monocyte chemotactic protein-1 gene expression by oxidized low-density lipoprotein: relevance to ischemic heart failure".American Journal of Physiology. Cell Physiology.302(1): C165-77.doi:10.1152/ajpcell.00116.2011.PMID21900689.S2CID9801961.
  33. ^Cuesta S, Kireev R, Forman K, García C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA (December 2010). "Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8)".Experimental Gerontology.45(12): 950–6.doi:10.1016/j.exger.2010.08.016.PMID20817086.S2CID42491323.
[edit]

Further reading

[edit]