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]
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
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MKVSAALLCL | LLIAATFIPQ | GLAQPDAINA | PVTCCYNFTN | RKISVQRLAS | ||||
YRRITSSKCP | KEAVIFKTIV | AKEICADPKQ | KWVQDSMDHL | DKQTQTPKT |
Molekulska biologija
urediCCL2 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
urediU 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
urediU 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
urediCCL2 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
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Vanjski linkovi
uredi- Lokacija ljudskog genoma CCL2 i stranica sa detaljima o genu CCL2 u UCSC Genome Browseru.
Dopunska literatura
uredi- 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. ISBN 978-1-4684-6011-7. PMID 1661560.
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- Sell H, Eckel J (juni 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. S2CID 33827660.