CXCL9
Hemokinski ligand 9 (C-X-C motiv) jest mali citokin koji je kod ljudi kodiran genom CXCL9 sa hromosoma 4. Pripada porodici hemokina CXC koja je također poznata kao monokin induciran gama interferonom (MIG). CXCL9 je jedan od hemokina koji ima ulogu da inducira hemotaksiju, promovira diferencijaciju i umnožavanje leukocita i uzrokuje ekstravazaciju tkiva.[5]
Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 125 aminokiselina, а molekulska težina 14.019 Da.[6]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MKKSGVLFLL | GIILLVLIGV | QGTPVVRKGR | CSCISTNQGT | IHLQSLKDLK | ||||
QFAPSPSCEK | IEIIATLKNG | VQTCLNPDSA | DVKELIKKWE | KQVSQKKKQK | ||||
NGKKHQKKKV | LKVRKSQRSR | QKKTT |
Funkcija
[uredi | uredi izvor]Receptor CXCL9 / CXCR3 regulira imunsku migraciju ćelija, diferencijaciju i aktivaciju. Imunska reaktivnost se javlja regrutacijom imunskih ćelija, kao što su citotoksični limfociti (CTL), prirodne ćelije ubice (NK) ćelije, NKT-ćelije i makrofagi. Th1-polarizacija također aktivira imunske ćelije kao odgovor na IFN-γ.[7] Tumor-infiltrirajući limfociti su ključ za kliničke ishode i predviđanje odgovora na inhibitore kontrolnih tačaka.[8] Studije in vivo sugeriraju da ima tumorogenu ulogu, povećanjem proliferacije tumora i metastaza. CXCL9 pretežno posreduje limfocitnu infiltraciju u žarišna mjesta i potiskuje rast tumora.[9]
Na ljudskom hromosomu 4, sko je povezan sa dva druga CXC hemokinska gena pod nazivom CXCL10 i CXCL11, čiji se geni nalaze blizu gena za CXCL9.[10][11] CXCL9, CXCL10 i CXCL11 svi izazivaju svoje hemotaksijske funkcije interakcijom sa hemokinskim receptorom CXCR3.[12]
Biomarkeri
[uredi | uredi izvor]Pokazalo se da su CXCL9, CXCL-10 i CXCL-11 validni biomarkeri za razvoj srčane insuficijencije i disfunkcije lijeve komore, sugerirajući naglašenu patofiziološku vezu između nivoa ovih hemokina i razvoja remodeliranih srčanih bolesti.[13][14]
Ovaj hemokin je također povezan kao biomarker za dijagnosticiranje infekcija Q-groznice.[15]
Interakcije
[uredi | uredi izvor]Pokazalo se da CXCL9 ima interakcije sa CXCR3.[16][17]
CXCL9 u imunskim reakcijama
[uredi | uredi izvor]Za diferencijaciju imunskih ćelija, neki izvještaji pokazuju da CXCL9 dovodi do Th1polarizacije preko CXCR3.[18] U in vivo modelu Zohara et al. pokazano je da CXCL9 dovodi do povećane transkripcije T-bet i RORγ, što dovodi do polarizacije Foxp3 –x regulatornih (Tr1) ćelija tipa 1 ili T pomoćnih ćelija 17 (Th17) iz nevinih (neupotrebljenih) T-ćelija preko fosforilacija STAT1, STAT4 i STAT5.[18]
Nekoliko studija je pokazalo da makrofagi povezani sa neoplazmama (TAM) imaju modulatorne aktivnosti u TME, a osa CXCL9 / CXCR3 utiče na polarizaciju TAM-a. TAM-ovi imaju suprotne efekte; M1 za antitumorske, a M2 za protumorske aktivnosti. Oghumu et al. pojasnili su da su miševi s nedostatkom CXCR3 pokazali povećanu proizvodnju receptora interleukina IL-4 i polarizaciju M2 u modelu raka dojke kod miša, te smanjeni urođeni i imunski posredovani antitumorski odgovor.[19]
Za aktivaciju imunskih ćelija, CXCL9 ih stimulira putem Th1-polarizacija i aktivacije. Th1-ćelije proizvode IFN-γ, TNF- α, IL-2 i pojačavaju antitumorsku imunost, stimulacijom CTL-a, NK-ćelija i makrofaga.[20] IFN-γ-ovisna petlja imunske aktivacije također podstiče oslobađanje CXCL9.
Imunske ćelije, kao što su Th1, CTL, NK-ćelije i NKT-ćelije, pokazuju antitumorski efekat protiv karcinomskih ćelija putem parakrinih CXCL9 / CXCR3 u tumorskim modelima.[9]
CXCL9/CXCR3 i PDL-1/PD-1
[uredi | uredi izvor]Odnos između CXCL9 / CXCR3 i PDL-1 / PD-1 važno je područje istraživanja. Programirana ćelijska smrt-1 je snažnije izražena na T-ćelijama tumora, nego na T-ćelijama u perifernoj krvi i terapija anti-PD-1 može inhibirati „imunski bijeg“ i imunsku aktivaciju.[21] Peng et al. pokazali su da anti-PD-1 ne samo da može povećati regresiju tumora posredovanu T-ćelijama, već i povećati ekspresiju IFN-γ, ali ne i CXCL9 za ćelije izvedene iz koštane srži.[21] Blokada PDL-1 / PD-1 ose u T-ćelijama može pokrenuti pozitivnu povratnu petlju na mjesto tumora kroz osu CXCL9 / CXCR3. Također. korištenjem antitijela anti-CTLA4, ova osovina je značajno povećana u lezijama prije tretmana melanoma kod pacijenata s dobrim kliničkim odgovorom nakon primjene ipilimumaba.[22]
CXCL9 i melanom
[uredi | uredi izvor]CXCL9 je takođe identifikovan kao kandidatski biomarker za usvajanje terapija transferom T-ćelija u metastatski melanom.[23] Uloga CXCL9 / CXCR3 u TME i imunskom odgovoru ima ključnu važnostu aktivaciji putem parakrine signalizacije, utičući na efikasnost liječenja karcinoma.[5]
Reference
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029417 - Ensembl, maj 2017
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- ^ Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, Alaparthy S, Berman D, Jure-Kunkel M, Siemers NO, Jackson JR, Shahabi V (juli 2012). "An immune-active tumor microenvironment favors clinical response to ipilimumab". Cancer Immunology, Immunotherapy. 61 (7): 1019–31. doi:10.1007/s00262-011-1172-6. PMID 22146893. S2CID 8464711.
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Dopunska literatura
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- Erdel M, Laich A, Utermann G, Werner ER, Werner-Felmayer G (1998). "The human gene encoding SCYB9B, a putative novel CXC chemokine, maps to human chromosome 4q21 like the closely related genes for MIG (SCYB9) and INP10 (SCYB10)". Cytogenetics and Cell Genetics. 81 (3–4): 271–2. doi:10.1159/000015043. PMID 9730616. S2CID 46846304.
- Jenh CH, Cox MA, Kaminski H, Zhang M, Byrnes H, Fine J, Lundell D, Chou CC, Narula SK, Zavodny PJ (april 1999). "Cutting edge: species specificity of the CC chemokine 6Ckine signaling through the CXC chemokine receptor CXCR3: human 6Ckine is not a ligand for the human or mouse CXCR3 receptors". Journal of Immunology. 162 (7): 3765–9. PMID 10201891.
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Vanjski linkovi
[uredi | uredi izvor]- Lokacija ljudskog genoma CXCL9 i stranica sa detaljima o genu CXCL9 u UCSC Genome Browseru.