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
urediDužina 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
urediReceptor 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
urediPokazalo 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
urediPokazalo se da CXCL9 ima interakcije sa CXCR3.[16][17]
CXCL9 u imunskim reakcijama
urediZa 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
urediOdnos 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
urediCXCL9 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
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000138755 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029417 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b Tokunaga R, Zhang W, Naseem M, Puccini A, Berger MD, Soni S, McSkane M, Baba H, Lenz HJ (februar 2018). "CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - A target for novel cancer therapy". Cancer Treatment Reviews. 63: 40–47. doi:10.1016/j.ctrv.2017.11.007. PMC 5801162. PMID 29207310.
- ^ "UniProt, Q07325" (jezik: engleski). Pristupljeno 24. 10. 2021.
- ^ Schoenborn, Jamie R.; Wilson, Christopher B. (2007), "Regulation of Interferon‐γ During Innate and Adaptive Immune Responses", Advances in Immunology, Elsevier, 96: 41–101, doi:10.1016/s0065-2776(07)96002-2, ISBN 9780123737090, PMID 17981204
- ^ Fernandez-Poma SM, Salas-Benito D, Lozano T, Casares N, Riezu-Boj JI, Mancheño U, Elizalde E, Alignani D, Zubeldia N, Otano I, Conde E, Sarobe P, Lasarte JJ, Hervas-Stubbs S (juli 2017). "+ T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy". Cancer Research. 77 (13): 3672–3684. doi:10.1158/0008-5472.CAN-17-0236. PMID 28522749.
- ^ a b Gorbachev, A. V.; Kobayashi, H.; Kudo, D.; Tannenbaum, C. S.; Finke, J. H.; Shu, S.; Farber, J. M.; Fairchild, R. L. (15. 2. 2007). "CXC Chemokine Ligand 9/Monokine Induced by IFN- Production by Tumor Cells Is Critical for T Cell-Mediated Suppression of Cutaneous Tumors". The Journal of Immunology. 178 (4): 2278–2286. doi:10.4049/jimmunol.178.4.2278. ISSN 0022-1767. PMID 17277133.
- ^ Lee HH, Farber JM (1996). "Localization of the gene for the human MIG cytokine on chromosome 4q21 adjacent to INP10 reveals a chemokine "mini-cluster"". Cytogenetics and Cell Genetics. 74 (4): 255–8. doi:10.1159/000134428. PMID 8976378.
- ^ O'Donovan N, Galvin M, Morgan JG (1999). "Physical mapping of the CXC chemokine locus on human chromosome 4". Cytogenetics and Cell Genetics. 84 (1–2): 39–42. doi:10.1159/000015209. PMID 10343098. S2CID 8087808.
- ^ Tensen CP, Flier J, Van Der Raaij-Helmer EM, Sampat-Sardjoepersad S, Van Der Schors RC, Leurs R, Scheper RJ, Boorsma DM, Willemze R (maj 1999). "Human IP-9: A keratinocyte-derived high affinity CXC-chemokine ligand for the IP-10/Mig receptor (CXCR3)". The Journal of Investigative Dermatology. 112 (5): 716–22. doi:10.1046/j.1523-1747.1999.00581.x. PMID 10233762.
- ^ Altara R, Gu YM, Struijker-Boudier HA, Thijs L, Staessen JA, Blankesteijn WM (2015). "Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study". PLOS ONE. 10 (10): e0141394. Bibcode:2015PLoSO..1041394A. doi:10.1371/journal.pone.0141394. PMC 4624781. PMID 26506526.
- ^ Altara R, Manca M, Hessel MH, Gu Y, van Vark LC, Akkerhuis KM, Staessen JA, Struijker-Boudier HA, Booz GW, Blankesteijn WM (august 2016). "CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study". Journal of Cardiovascular Translational Research. 9 (4): 302–14. doi:10.1007/s12265-016-9703-3. PMID 27271043. S2CID 41188765.
- ^ Jansen AF, Schoffelen T, Textoris J, Mege JL, Nabuurs-Franssen M, Raijmakers RP, Netea MG, Joosten LA, Bleeker-Rovers CP, van Deuren M (august 2017). "CXCL9, a promising biomarker in the diagnosis of chronic Q fever". BMC Infectious Diseases. 17 (1): 556. doi:10.1186/s12879-017-2656-6. PMC 5551022. PMID 28793883.
- ^ Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L, Sagrinati C, Mazzinghi B, Orlando C, Maggi E, Marra F, Romagnani S, Serio M, Romagnani P (juni 2003). "An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4". The Journal of Experimental Medicine. 197 (11): 1537–49. doi:10.1084/jem.20021897. PMC 2193908. PMID 12782716.
- ^ Weng Y, Siciliano SJ, Waldburger KE, Sirotina-Meisher A, Staruch MJ, Daugherty BL, Gould SL, Springer MS, DeMartino JA (juli 1998). "Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors". The Journal of Biological Chemistry. 273 (29): 18288–91. doi:10.1074/jbc.273.29.18288. PMID 9660793.
- ^ a b Zohar Y, Wildbaum G, Novak R, Salzman AL, Thelen M, Alon R, Barsheshet Y, Karp CL, Karin N (maj 2014). "CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis". The Journal of Clinical Investigation. 124 (5): 2009–22. doi:10.1172/JCI71951. PMC 4001543. PMID 24713654.
- ^ Oghumu S, Varikuti S, Terrazas C, Kotov D, Nasser MW, Powell CA, Ganju RK, Satoskar AR (septembar 2014). "CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model". Immunology. 143 (1): 109–19. doi:10.1111/imm.12293. PMC 4137960. PMID 24679047.
- ^ Mosser DM, Edwards JP (decembar 2008). "Exploring the full spectrum of macrophage activation". Nature Reviews. Immunology. 8 (12): 958–69. doi:10.1038/nri2448. PMC 2724991. PMID 19029990.
- ^ a b Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizée G, Radvanyi L, Hwu P (oktobar 2012). "PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines". Cancer Research. 72 (20): 5209–18. doi:10.1158/0008-5472.CAN-12-1187. PMC 3476734. PMID 22915761.
- ^ 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.
- ^ Bedognetti D, Spivey TL, Zhao Y, Uccellini L, Tomei S, Dudley ME, Ascierto ML, De Giorgi V, Liu Q, Delogu LG, Sommariva M, Sertoli MR, Simon R, Wang E, Rosenberg SA, Marincola FM (oktobar 2013). "CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2". British Journal of Cancer. 109 (9): 2412–23. doi:10.1038/bjc.2013.557. PMC 3817317. PMID 24129241.
Dopunska literatura
uredi- Farber JM (juli 1990). "A macrophage mRNA selectively induced by gamma-interferon encodes a member of the platelet factor 4 family of cytokines". Proceedings of the National Academy of Sciences of the United States of America. 87 (14): 5238–42. Bibcode:1990PNAS...87.5238F. doi:10.1073/pnas.87.14.5238. PMC 54298. PMID 2115167.
- Liao F, Rabin RL, Yannelli JR, Koniaris LG, Vanguri P, Farber JM (novembar 1995). "Human Mig chemokine: biochemical and functional characterization". The Journal of Experimental Medicine. 182 (5): 1301–14. doi:10.1084/jem.182.5.1301. PMC 2192190. PMID 7595201.
- Farber JM (april 1993). "HuMig: a new human member of the chemokine family of cytokines". Biochemical and Biophysical Research Communications. 192 (1): 223–30. doi:10.1006/bbrc.1993.1403. PMID 8476424.
- 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.
- Rabin RL, Park MK, Liao F, Swofford R, Stephany D, Farber JM (april 1999). "Chemokine receptor responses on T cells are achieved through regulation of both receptor expression and signaling". Journal of Immunology. 162 (7): 3840–50. PMID 10201901.
- Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH (decembar 1999). "Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver". Journal of Immunology. 163 (11): 6236–43. PMID 10570316.
- Jinquan T, Jing C, Jacobi HH, Reimert CM, Millner A, Quan S, Hansen JB, Dissing S, Malling HJ, Skov PS, Poulsen LK (august 2000). "CXCR3 expression and activation of eosinophils: role of IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma". Journal of Immunology. 165 (3): 1548–56. doi:10.4049/jimmunol.165.3.1548. PMID 10903763.
- Loetscher P, Pellegrino A, Gong JH, Mattioli I, Loetscher M, Bardi G, Baggiolini M, Clark-Lewis I (februar 2001). "The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3". The Journal of Biological Chemistry. 276 (5): 2986–91. doi:10.1074/jbc.M005652200. PMID 11110785.
- Romagnani P, Annunziato F, Lazzeri E, Cosmi L, Beltrame C, Lasagni L, Galli G, Francalanci M, Manetti R, Marra F, Vanini V, Maggi E, Romagnani S (februar 2001). "Interferon-inducible protein 10, monokine induced by interferon gamma, and interferon-inducible T-cell alpha chemoattractant are produced by thymic epithelial cells and attract T-cell receptor (TCR) alphabeta+ CD8+ single-positive T cells, TCRgammadelta+ T cells, and natural killer-type cells in human thymus". Blood. 97 (3): 601–7. doi:10.1182/blood.V97.3.601. PMID 11157474.
- Dwinell MB, Lügering N, Eckmann L, Kagnoff MF (januar 2001). "Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells". Gastroenterology. 120 (1): 49–59. doi:10.1053/gast.2001.20914. PMID 11208713.
- Lambeir AM, Proost P, Durinx C, Bal G, Senten K, Augustyns K, Scharpé S, Van Damme J, De Meester I (august 2001). "Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family". The Journal of Biological Chemistry. 276 (32): 29839–45. doi:10.1074/jbc.M103106200. PMID 11390394.
- Stoof TJ, Flier J, Sampat S, Nieboer C, Tensen CP, Boorsma DM (juni 2001). "The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells". The British Journal of Dermatology. 144 (6): 1114–20. doi:10.1046/j.1365-2133.2001.04220.x. PMID 11422029. S2CID 26364400.
- Campbell JD, Stinson MJ, Simons FE, Rector ES, HayGlass KT (juli 2001). "In vivo stability of human chemokine and chemokine receptor expression". Human Immunology. 62 (7): 668–78. doi:10.1016/S0198-8859(01)00260-9. PMID 11423172.
- Scapini P, Laudanna C, Pinardi C, Allavena P, Mantovani A, Sozzani S, Cassatella MA (juli 2001). "Neutrophils produce biologically active macrophage inflammatory protein-3alpha (MIP-3alpha)/CCL20 and MIP-3beta/CCL19". European Journal of Immunology. 31 (7): 1981–8. doi:10.1002/1521-4141(200107)31:7<1981::AID-IMMU1981>3.0.CO;2-X. PMID 11449350.
- Gillitzer R (august 2001). "Inflammation in human skin: a model to study chemokine-mediated leukocyte migration in vivo". The Journal of Pathology. 194 (4): 393–4. doi:10.1002/1096-9896(200108)194:4<393::AID-PATH907>3.0.CO;2-7. PMID 11523044.
- Romagnani P, Rotondi M, Lazzeri E, Lasagni L, Francalanci M, Buonamano A, Milani S, Vitti P, Chiovato L, Tonacchera M, Bellastella A, Serio M (juli 2002). "Expression of IP-10/CXCL10 and MIG/CXCL9 in the thyroid and increased levels of IP-10/CXCL10 in the serum of patients with recent-onset Graves' disease". The American Journal of Pathology. 161 (1): 195–206. doi:10.1016/S0002-9440(10)64171-5. PMC 1850693. PMID 12107104.
Vanjski linkovi
uredi- Lokacija ljudskog genoma CXCL9 i stranica sa detaljima o genu CXCL9 u UCSC Genome Browseru.