Wikipedia

CCL2

Hemokinski (C-C motivni) ligand 2 (CCL2) , znan i kao monocitni hemoatraktantni protein 1 (MCP1) i mali inducibilni citokin A2. CCL2 je mali citokin koji pripada porodici CC hemokina. CCL2 regrutuje monocite, memorijske T-ćelije i dendritske ćelije na mjesta upala nastalih ozljedom tkiva ili infekcijom.[5][6]

CCL2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1DOK, 1DOL, 1DOM, 1DON, 1ML0, 2BDN, 2NZ1, 4DN4, 3IFD, 4R8I, 4ZK9

Identifikatori
AliasiCCL2
Vanjski ID-jeviOMIM: 158105 MGI: 108224 HomoloGene: 2245 GeneCards: CCL2
Lokacija gena (čovjek)
Hromosom 17 (čovjek)
Hrom.Hromosom 17 (čovjek)[1]
Hromosom 17 (čovjek)
Genomska lokacija za CCL2
Genomska lokacija za CCL2
Bend17q12Početak34,255,274 bp[1]
Kraj34,257,208 bp[1]
Lokacija gena (miš)
Hromosom 11 (miš)
Hrom.Hromosom 11 (miš)[2]
Hromosom 11 (miš)
Genomska lokacija za CCL2
Genomska lokacija za CCL2
Bend11 C|11 49.9 cMPočetak81,992,671 bp[2]
Kraj81,994,226 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• signaling receptor binding
• protein kinase activity
• cytokine activity
• GO:0001948, GO:0016582 vezivanje za proteine
• chemokine activity
• CCR2 chemokine receptor binding
• CCR chemokine receptor binding
Ćelijska komponenta• extracellular region
• Vanćelijsko
• intracellular anatomical structure
Biološki proces• GO:1904089 negative regulation of neuron apoptotic process
• viral genome replication
• negative regulation of natural killer cell chemotaxis
• protein phosphorylation
• cell surface receptor signaling pathway
• humoral immune response
• Angiogeneza
• positive regulation of ERK1 and ERK2 cascade
• animal organ morphogenesis
• cellular homeostasis
• cellular response to fibroblast growth factor stimulus
• GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 positive regulation of GTPase activity
• inflammatory response
• G protein-coupled receptor signaling pathway
• monocyte chemotaxis
• G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger
• GO:1904579 cellular response to organic cyclic compound
• Hemotaksija
• Ćelijska adhezija
• GO:0046730, GO:0046737, GO:0046738, GO:0046736 Imuni odgovor
• regulation of cell shape
• lipopolysaccharide-mediated signaling pathway
• receptor signaling pathway via JAK-STAT
• response to bacterium
• protein kinase B signaling
• astrocyte cell migration
• negative regulation of glial cell apoptotic process
• PERK-mediated unfolded protein response
• MAPK cascade
• positive regulation of calcium ion import
• cytoskeleton organization
• GO:0072468 Transdukcija signala
• regulation of signaling receptor activity
• neutrophil chemotaxis
• helper T cell extravasation
• macrophage chemotaxis
• positive regulation of T cell activation
• positive regulation of nitric-oxide synthase biosynthetic process
• chemokine-mediated signaling pathway
• cellular response to lipopolysaccharide
• cellular response to interferon-gamma
• cellular response to interleukin-1
• cellular response to tumor necrosis factor
• positive regulation of apoptotic cell clearance
• cytokine-mediated signaling pathway
• negative regulation of vascular endothelial cell proliferation
• GO:1990376 negative regulation of G1/S transition of mitotic cell cycle
• positive regulation of endothelial cell apoptotic process
• eosinophil chemotaxis
• lymphocyte chemotaxis
• Nocicepcija
• positive regulation of synaptic transmission, glutamatergic
• positive regulation of NMDA glutamate receptor activity
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

6347

20293

Ensembl

ENSG00000108691

ENSMUSG00000035352

UniProt

P13500

Q62401

RefSeq (mRNK)

NM_002982

NM_011331

RefSeq (bjelančevina)

NP_002973

NP_035461

Lokacija (UCSC)Chr 17: 34.26 – 34.26 MbChr 11: 81.99 – 81.99 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 99 aminokiselina, a molekulska težina

11.025 Da.[7].

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

1020304050
MKVSAALLCLLLIAATFIPQGLAQPDAINAPVTCCYNFTNRKISVQRLAS
YRRITSSKCPKEAVIFKTIVAKEICADPKQKWVQDSMDHLDKQTQTPKT

Molekulska biologija

uredi

CCL2 je monomerni polipeptid, sa molekulskom težinom od približno 13-15 kDa, ovisno o nivoima glikozilacije.[8] CCL2 je usidren u plazemamembranu endotelnih ćelija, pomoću bočnih lanaca glikozaminoglikanskih proteoglikana. CCL2 se primarno izlučuje iz monocita, makrofaga i dendritskih ćelija. Glavni je induktor gena CCL2 je faktor rasta izveden iz trombocita.

Na površini ćelije, CCR2 i CCR4 su dva receptora koji vežu CCL2.[9]

CCL2 ima hemotaksijsku aktivnost za monocite i bazofile. Međutim, ne privlači neutrofile ili eozinofili. Nakon delecije N-terminalnog ostatka, CCL2 gubi atraktivnost za bazofile i postaje hemoatraktant eozinofila. Bazofili i mastociti koji se liječe CCL2-om, oslobađaju svoje granule u međućelijski prostor. Ovaj se efekt može pojačati i prethodnim tretmanom IL-3 ili čak drugim citokinima.[10][11] CCL2 pojačava antitumorsku aktivnost monocita i neophodan je za stvaranje granuloma 12. CCL2 protein postaje CCR2 antagonist kada se cijepi pomoću metaloproteinaza MMP-12.[12]

CCL2 može se naći na mjestima nicanja zuba i propadanja kostiju. U kosti se CCL2 eksprimira sa zrelim osteoklastom i osteoblastom i pod nadzorom je nuklearnog faktora κB (NFκB). U ljudskim osteoklastima, CCL2 i RANTES (regulirani na aktivaciju normalnih eksprimiranih i izlučenih T-ćelija). I MCP-1 i RANTES indukuju stvaranje TRAP-pozitivnih, multijedarnih ćelija iz monocita tretiranih M-CSF u odsustvu RANKL-a, ali su stvorili osteoklaste kojima nedostaje ekspresija katepsina K i resorptivna sposobnost. Predlaže se da CCL2 i RANTES djeluju kao autokrina petlja u diferencijaciji ljudskih osteoklasta.[13]

Hemokin CCL2 također eksprimiraju neuroni, astrociti i mikroglija. Ekspresija CCL2 u neuronima uglavnom je u moždanom korteksu, globus pallidus, hipokampusu, parakomorskim i supraoptičnim hipotalamusnim jezgrima, bočnim dijelovima hipotalamusa, substantia nigra, jezgrima lica, motornim i kičmenim trigeminusnim jezgrima, gigantoćelijskom mrežastom jezgru i u Purkinjeovim ćelijama u malom mozgu.[14]

Genomika

uredi

U ljudskom genomu, CCL2 i geni mnogih drugih CC hemokina nalaze se na hromosomu 17 (17q11.2-q21.1).[15] Raspon gena je 1.927 baza, a CCL2 gen nalazi se na lancu Watson (plus). Gen CCL2 ima tri egzona i dva introna. Proteinski prekursor CCL2 sadrži signalni peptid od 23 aminokiseline. Zreli CCL2 dug je 76 aminokiselina.[16][17] Predviđena težina CCL2 je 11,025 kiloDaltona (kDa).

Populacijska genetika

uredi

U ljudi, nivo CCL2 može znatno varirati. Kod kavkazoida evropskog porijekla multivarijabilno prilagođena nasljednost koncentracija CCL2 iznosi čak 0,37 u krvnoj plazmi i 0,44 – u serumu.[18][19]

Klinički značaj

uredi

CCL2 je uključen u patogeneze nekoliko bolesti koje karakterišu monocitni infiltrati, kao što su psorijaza, reumatoidni artritis i ateroskleroza.[20]

Primjena antitijela na CCL2 u modelu glomerulonefritis smanjuje infiltraciju makrofaga i T-ćelija, smanjuje stvaranje polumjesečastih struktura, kao i ožiljke i oštećenje bubrega.[21]

CCL2 je uključen u neuroupalne procese koji se odvijaju kod različitih bolesti centralnog nervnog sistema (CNS), koje karakterizira degeneracija neurona.[22] Ekspresija CCL2 u ćelijama glije povećana je kod epilepsije,[23][24] ishemije mozga[25] Alzhrimerove bolesti[26] eksperimentalnog autoimunskog encefalomijelitisa (EAE)[27] i taumatske povrede mozga.[28]

Na hipometilaciju CpG mjesta unutar promotorske regije CCL2 utiču visoki nivoi glukoze u krvi i TG, koji povećavaju nivo CCL2 u krvnom serumu. Kasnije ima važnu ulogu u vaskularnim komplikacijama dijabetesa tipa 2.[29]

CCL2 indukcira ekspresiju amilina, oputem MAPK3 ERK1/ERK2/ JNK–AP1 i NF-κB povezanih signalnih puteva neovisnih o CCR2. Povećanje regulacije amilina pomoću CCL2 doprinosi povišenju rezistencije aminina u plazmi i rezistencije na insulin kod gojaznosti.[30]

Adipociti luče različite adipokine, koji mogu biti uključeni u negativni unakrsni odgovor između masnog tkiva i skeletnih mišića. CCL2 umanjuje signal inzulina u ćelijama skeletnih mišića aktiviranjem ERK1/2 u dozama sličnim njegovim fiziološkim koncentracijama u plazmi (200 pg/ml), ali ne uključuje aktivaciju NF-κB puta. CCL2 je značajno smanjio unos glukoze stimuliran insulinom u miocitima. CCL2 može predstavljati molekulsku vezu u negativnom unakrsnom odgovoru između masnog tkiva i koštanog mišića, dodijelivši CCL2 potpuno novu važnu ulogu osim upala.[31]

Inkubacija HL-1 kardiomiocita i ljudskih miocita sa oksidovanim LDL inducirala je ekspresiju moždani natriuretski peptid (BNP) i gena CCL2, dok nativni LDL (N-LDL) nije imao efekta.[32]

Tretman melatoninom kod starih miševa sa starosnom upalom jetre smanjio je ekspresiju iRNK TNF-α, IL-1β, HO (HO-1 i HO-2), iNOS, CCL2, NF-κB1, NF-κB2 i NKAP kod starih muških miševa . Ekspresija proteina TNF-α, IL-1β također je smanjena i povećana IL-10 liječenjem melatoninom. Egzogena primjena melatonina uspjela je smanjiti upalu.[33]

Reference

uredi
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000108691 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035352 - Ensembl, maj 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. ^ 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. PMC 43639. PMID 8170963.
  6. ^ Xu LL, Warren MK, Rose WL, Gong W, Wang JM (septembar 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. PMID 8830793. S2CID 24481789.
  7. ^ "UniProt, P13500". Pristupljeno June 26, 2021.
  8. ^ 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. PMC 6052833. PMID 29375123.
  9. ^ Craig MJ, Loberg RD (decembar 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. S2CID 24366011.
  10. ^ Conti P, Boucher W, Letourneau R, Feliciani C, Reale M, Barbacane RC, Vlagopoulos P, Bruneau G, Thibault J, Theoharides TC (novembar 1995). "Monocyte chemotactic protein-1 provokes mast cell aggregation and [3H]5HT release". Immunology. 86 (3): 434–40. PMC 1383948. PMID 8550082.
  11. ^ Bischoff SC, Krieger M, Brunner T, Dahinden CA (maj 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.
  12. ^ Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM (oktobar 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. PMID 18660381.
  13. ^ 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. PMID 15722361. S2CID 22756184.
  14. ^ 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. PMID 16025454. S2CID 22254007.
  15. ^ Mehrabian M, Sparkes RS, Mohandas T, Fogelman AM, Lusis AJ (januar 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.
  16. ^ Yoshimura T, Yuhki N, Moore SK, Appella E, Lerman MI, Leonard EJ (februar 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. S2CID 7097272.
  17. ^ Furutani Y, Nomura H, Notake M, Oyamada Y, Fukui T, Yamada M, Larsen CG, Oppenheim JJ, Matsushima K (februar 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.
  18. ^ 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. PMID 16116069. S2CID 12320863.
  19. ^ Bielinski SJ, Pankow JS, Miller MB, Hopkins PN, Eckfeldt JH, Hixson J, Liu Y, Register T, Myers RH, Arnett DK (decembar 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. S2CID 8242432.
  20. ^ Xia M, Sui Z (mart 2009). "Recent developments in CCR2 antagonists". Expert Opinion on Therapeutic Patents. 19 (3): 295–303. doi:10.1517/13543770902755129. PMID 19441905. S2CID 45028620.
  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. PMC 2196251. PMID 9104823.
  22. ^ Gerard C, Rollins BJ (februar 2001). "Chemokines and disease". Nature Immunology. 2 (2): 108–15. doi:10.1038/84209. PMID 11175802. S2CID 28336866.
  23. ^ Foresti ML, Arisi GM, Katki K, Montañez A, Sanchez RM, Shapiro LA (decembar 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.
  24. ^ Fabene PF, Bramanti P, Constantin G (juli 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. S2CID 5121343.
  25. ^ Kim JS, Gautam SC, Chopp M, Zaloga C, Jones ML, Ward PA, Welch KM (februar 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. S2CID 45538922.
  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. PMC 3684802. PMID 20205643.
  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. PMID 8472896. S2CID 13552110.
  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. PMC 2949175. PMID 20029451.
  29. ^ Liu ZH, Chen LL, Deng XL, Song HJ, Liao YF, Zeng TS, Zheng J, Li HQ (juni 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. S2CID 14613351.
  30. ^ Cai K, Qi D, Hou X, Wang O, Chen J, Deng B, Qian L, Liu X, Le Y (maj 2011). Fadini GP (ured.). "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. PMC 3092759. PMID 21589925.
  31. ^ Sell H, Dietze-Schroeder D, Kaiser U, Eckel J (maj 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.
  32. ^ Chandrakala AN, Sukul D, Selvarajan K, Sai-Sudhakar C, Sun B, Parthasarathy S (januar 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.
  33. ^ Cuesta S, Kireev R, Forman K, García C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA (decembar 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. S2CID 42491323.

Vanjski linkovi

uredi

Dopunska literatura

uredi
Preuzeto iz "https://bs.wikipedia.org/w/index.php?title=CCL2&oldid=3672938"