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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/01/20 13:50:18」(JST)

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Chemokine receptor CXCR3 is a Gα_i protein-coupled receptor in the CXC chemokine receptor family. Other names for CXCR3 are G protein-coupled receptor 9 (GPR9) and CD183. There are two variants of CXCR3: CXCR3-A binds to the CXC chemokines CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC)^[1] whereas CXCR3-B can also bind to CXCL4 in addition to CXCL9, CXCL10, and CXCL11.^[2]

Expression

CXCR3 is expressed primarily on activated T lymphocytes and NK cells,^[3] and some epithelial cells and some endothelial cells. CXCR3 and CCR5 are preferentially expressed on Th1 cells, whereas Th2 cells favor the expression of CCR3 and CCR4. CXCR3 ligands that attract Th1 cells can concomitantly block the migration of Th2 cells in response to CCR3 ligands, thus enhancing the polarization of effector T cell recruitment.

Signal transduction

Binding of CXCL9, CXCL10, and CXCL11 to CXCR3 is able to elicit increases in intracellular Ca²⁺⁺ levels and activate phosphoinositide 3-kinase and mitogen-activated protein kinase (MAPK).^[4] Detailed signaling pathway has not yet been established, but may include the same enzymes that were identified in the signaling cascade induced by other chemokine receptors.

Function

CXCR3 is able to regulate leukocyte trafficking. Binding of chemokines to CXCR3 induces various cellular responses, most notably integrin activation, cytoskeletal changes and chemotactic migration. CXCR3-ligand interaction attracts Th1 cells and promotes Th1 cell maturation.

As a consequence of chemokine-induced cellular desensitization (phosphorylation-dependent receptor internalization), cellular responses are typically rapid and short in duration. Cellular responsiveness is restored after dephosphorylation of intracellular receptors and subsequent recycling to the cell surface. A hallmark of CXCR3 is its prominent expression in in vitro cultured effector/memory T cells, and in T cells present in many types of inflamed tissues. In addition, CXCL9, CXCL10 and CXCL11 are commonly produced by local cells in inflammatory lesion, suggesting that CXCR3 and its chemokines participate in the recruitment of inflammatory cells.^[5] Additionally, CXCR3 has been implicated in wound healing.^[6]

Disease

CXCR3 has been implicated in the following diseases, atherosclerosis,^[7] multiple sclerosis,^[8] pulmonary fibrosis,^[9] type 1 diabetes,^[10] autoimmune myasthenia gravis, nephrotoxic nephritis,^[11] acute cardiac allograft rejection^[12] and possibly Celiac Disease.^[13] Development of agents to block CXCR3-ligand interactions may provide new ways to treat these diseases.

Pharmacology

Recent reports indicate that there is a significant interest for the identification of small-molecule antagonists of CXCR3.^[14] Several small molecules ^[15] were found to constitute a promising series of functional antagonists of CXCR3 that could be developed into new therapeutic agents for the treatment of inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease,multiple sclerosis and diabetes. More recently the first QSAR study concerning antagonists of CXCR3 has been published in the literature. The in silico model provides a time- and cost-effective tool for the screening of existing and virtual libraries of small molecules as well as for designing of novel molecules of desired activity.^[16]

Interactions

CXCR3 has been shown to interact with CXCL9.^[2]^[17]

References

^ Clark-Lewis I, Mattioli I, Gong JH, Loetscher P (2003). "Structure-function relationship between the human chemokine receptor CXCR3 and its ligands". J. Biol. Chem. 278 (1): 289–95. doi:10.1074/jbc.M209470200. PMID 12417585.
^ ^a ^b 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 (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". J. Exp. Med. 197 (11): 1537–49. doi:10.1084/jem.20021897. PMC 2193908. PMID 12782716. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2193908/.
^ Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR (1998). "The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions". J. Clin. Invest. 101 (4): 746–54. doi:10.1172/JCI1422. PMC 508621. PMID 9466968. //www.ncbi.nlm.nih.gov/pmc/articles/PMC508621/.
^ Smit MJ, Verdijk P, van der Raaij-Helmer EM, Navis M, Hensbergen PJ, Leurs R, Tensen CP (2003). "CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C-dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3 kinase". Blood 102 (6): 1959–65. doi:10.1182/blood-2002-12-3945. PMID 12750173.
^ "Entrez Gene: CXCR3 chemokine (C-X-C motif) receptor 3". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2833.
^ Yates CC, Whaley D, Kulasekeran P, Hancock WW, Lu B, Bodnar R, Newsome J, Hebda PA, Wells A (2007). "Delayed and Deficient Dermal Maturation in Mice Lacking the CXCR3 ELR-Negative CXC Chemokine Receptor". Am. J. Pathol. 171 (2): 484–95. doi:10.2353/ajpath.2007.061092. PMC 1934531. PMID 17600132. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1934531/.
^ Mach F, Sauty A, Iarossi AS, Sukhova GK, Neote K, Libby P, Luster AD (1999). "Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells". J. Clin. Invest. 104 (8): 1041–50. doi:10.1172/JCI6993. PMC 408576. PMID 10525042. //www.ncbi.nlm.nih.gov/pmc/articles/PMC408576/.
^ Sørensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Rottman J, Sellebjerg F, Strieter RM, Frederiksen JL, Ransohoff RM (1999). "Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients". J. Clin. Invest. 103 (6): 807–15. doi:10.1172/JCI5150. PMC 408141. PMID 10079101. //www.ncbi.nlm.nih.gov/pmc/articles/PMC408141/.
^ Jiang D, Liang J, Hodge J, Lu B, Zhu Z, Yu S, Fan J, Gao Y, Yin Z, Homer R, Gerard C, Noble PW (2004). "Regulation of pulmonary fibrosis by chemokine receptor CXCR3". J. Clin. Invest. 114 (2): 291–9. doi:10.1172/JCI200416861. PMC 449741. PMID 15254596. //www.ncbi.nlm.nih.gov/pmc/articles/PMC449741/.
^ Frigerio S, Junt T, Lu B, Gerard C, Zumsteg U, Holländer GA, Piali L (2002). "Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis". Nat. Med. 8 (12): 1414–20. doi:10.1038/nm792. PMID 12415259.
^ Panzer U, Steinmetz OM, Paust HJ, Meyer-Schwesinger C, Peters A, Turner JE, Zahner G, Heymann F, Kurts C, Hopfer H, Helmchen U, Haag F, Schneider A, Stahl RA (2007). "Chemokine receptor CXCR3 mediates T cell recruitment and tissue injury in nephrotoxic nephritis in mice". J. Am. Soc. Nephrol. 18 (7): 2071–84. doi:10.1681/ASN.2006111237. PMID 17538187.
^ Hancock WW, Lu B, Gao W, Csizmadia V, Faia K, King JA, Smiley ST, Ling M, Gerard NP, Gerard C (2000). "Requirement of the Chemokine Receptor CXCR3 for Acute Allograft Rejection". J. Exp. Med. 192 (10): 1515–20. doi:10.1084/jem.192.10.1515. PMC 2193193. PMID 11085753. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2193193/.
^ Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A. (2008). "Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3". Gastroenterology 135 (1): 194–204.e3. doi:10.1053/j.gastro.2008.03.023. PMC 2653457. PMID 18485912. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2653457/.
^ Watson RJ, Allen DR, Birch HL, et al. (January 2008). "Development of CXCR3 antagonists. Part 3: Tropenyl and homotropenyl-piperidine urea derivatives". Bioorg. Med. Chem. Lett. 18 (1): 147–51. doi:10.1016/j.bmcl.2007.10.109. PMID 18032038.
^ Watson RJ, Allen DR, Birch HL, et al. (December 2007). "Development of CXCR3 antagonists. Part 2: Identification of 2-amino(4-piperidinyl)azoles as potent CXCR3 antagonists". Bioorg. Med. Chem. Lett. 17 (24): 6806–10. doi:10.1016/j.bmcl.2007.10.029. PMID 17964154.
^ Afantitis A, Melagraki G, Sarimveis H, Igglessi-Markopoulou O, Kollias G (July 2008). "A novel QSAR model for predicting the inhibition of CXCR3 receptor by 4-N-aryl-[1,4] diazepane ureas". Eur J Med Chem 44 (2): 877–84. doi:10.1016/j.ejmech.2008.05.028. PMID 18619714.
^ Weng, Y; Siciliano S J, Waldburger K E, Sirotina-Meisher A, Staruch M J, Daugherty B L, Gould S L, Springer M S, DeMartino J A (Jul. 1998). "Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors". J. Biol. Chem. (UNITED STATES) 273 (29): 18288–91. doi:10.1074/jbc.273.29.18288. ISSN 0021-9258. PMID 9660793.

External links

"Chemokine Receptors: CXCR3". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2214.
CD183+Antigen at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 成人におけるセリアック病の病因、疫学、および臨床症状 pathogenesis epidemiology and clinical manifestations of celiac disease in adults
2. 急性尿細管壊死の研究用バイオマーカーおよび評価 investigational biomarkers and the evaluation of acute tubular necrosis
3. シャーガス病：病理および病因 chagas disease pathology and pathogenesis
4. 若年性特発性関節炎：疫学と免疫病態学 juvenile idiopathic arthritis epidemiology and immunopathogenesis
5. ヘルパーT細胞サブセット：疾患における分化および役割 t helper subsets differentiation and role in disease

English Journal

Cyclophosphamide treatment induces rejection of established P815 mastocytoma by enhancing CD4 priming and intratumoral infiltration of P1E/H-2K(d) -specific CD8(+) T cells.

Rahir G1, Wathelet N, Hanoteau A, Henin C, Oldenhove G, Galuppo A, Lanaya H, Colau D, Mackay CR, Van den Eynde B, Moser M.Author information 1Department of Molecular Biology, Université Libre de Bruxelles, Gosselies, Belgium.AbstractThere is increasing evidence that the effect of chemotherapy on tumor growth is not cell autonomous but relies on the immune system. The objective of this study was therefore to decipher the cellular and molecular mechanisms underlying the role of innate and adaptive immunity in chemotherapy-induced tumor rejection. Treatment of DBA/2 mice bearing P815 mastocytoma with cyclophosphamide induced rejection and long-term protection in a CD4- and CD8-dependent manner. A population of inflammatory-type dendritic cells was dramatically expanded in the lymph nodes of mice that rejected the tumor and correlated with CD4-dependent infiltration, in tumor bed, of tumor-specific CD8(+) T lymphocytes. Our data point to a major role of CD4(+) T cells in inducing chemokine expression in the tumor, provoking migration of tumor-specific CXCR3(+) CD8(+) T lymphocytes. Importantly, the analysis of CD8(+) T cells specific to P1A/H-2L(d) and P1E/H-2K(d) revealed that cyclophosphamide altered the P815-specific CD8 T repertoire by amplifying the response specific to the mutated P1E antigen.
International journal of cancer. Journal international du cancer.Int J Cancer.2014 Jun 15;134(12):2841-52. doi: 10.1002/ijc.28617. Epub 2013 Nov 29.
There is increasing evidence that the effect of chemotherapy on tumor growth is not cell autonomous but relies on the immune system. The objective of this study was therefore to decipher the cellular and molecular mechanisms underlying the role of innate and adaptive immunity in chemotherapy-induced
PMID 24249003

Trafficking phenotype and production of granzyme B by double negative B cells (IgG(+)IgD(-)CD27(-)) in the elderly.

Bulati M1, Buffa S1, Martorana A1, Candore G1, Lio D1, Caruso C1, Colonna-Romano G2.Author information 1Immunosenescence Unit, Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory 211, 90134 Palermo, Italy.2Immunosenescence Unit, Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Corso Tukory 211, 90134 Palermo, Italy. Electronic address: giuseppina.colonnaromano@unipa.it.AbstractThe impairment of humoral immune response in elderly humans has been extensively demonstrated. We have reported the increase of memory B cells (IgG(+)IgD(-)CD27(-), double negative, DN) population in the elderly, in which there is also a typical inflammatory micro-environment. In order to evaluate whether this pro-inflammatory status could influence the trafficking phenotype of naïve/memory B cells, we have assessed the expression of CCR7, CCR6, CXCR3, CXCR4, CXCR5 and CD62L on naïve/memory B cell subpopulations in young and elderly subjects. Moreover, the combination of pro-inflammatory interleukin-21 (IL-21) and B cell receptor (BCR) stimulation enables B cells to produce and secrete granzyme B (GrB), which plays a critical role in early anti-viral immune responses, in the regulation of autoimmune mechanisms and in cancer immunosurveillance. Our data demonstrate that in the elderly, naïve/memory B cell populations present a different expression of the studied receptors that could be discussed in terms of "inflamm-aging". In particular IgG(+)IgD(-)CD27(-) DN B cells show a tissue trafficking phenotype and they can be stimulated to produce GrB.
Experimental gerontology.Exp Gerontol.2014 Jun;54:123-9. doi: 10.1016/j.exger.2013.12.011. Epub 2014 Jan 2.
The impairment of humoral immune response in elderly humans has been extensively demonstrated. We have reported the increase of memory B cells (IgG(+)IgD(-)CD27(-), double negative, DN) population in the elderly, in which there is also a typical inflammatory micro-environment. In order to evaluate w
PMID 24389059

C-X-C ligand 10 and C-X-C receptor 3 status can predict tamoxifen treatment response in breast cancer patients.

Hilborn E1, Sivik T, Fornander T, Stål O, Nordenskjöld B, Jansson A.Author information 1Division of Surgery and Clinical Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 581 85, Linköping, Sweden, erik.hilborn@liu.se.AbstractTo investigate the expression levels of CXCL10 and CXCR3 in tumors from breast cancer patients randomized to adjuvant tamoxifen treatment or no endocrine treatment, in order to further study the connection to prognosis and prediction of tamoxifen treatment outcome. Immunohistochemistry on tissue microarrays from 912 breast cancer patients randomized to tamoxifen or no endocrine treatment. CXCR3 status was found to be a prognostic tool in predicting distant recurrence, as well as reduced breast cancer-specific survival. In patients with estrogen receptor (ER)-positive tumors, tumors with strong CXCL10 levels had improved effect of tamoxifen treatment in terms of local recurrence-free survival [risk ratio (RR) 0.46 (95 % CI 0.25-0.85, P = 0.01)] compared with patients with tumors expressing weak CXCL10 expression. Further, patients with ER-positive tumors with strong CXCR3 expression had an improved effect of tamoxifen in terms of breast cancer-specific survival [RR 0.34 (95 % CI 0.19-0.62, P < 0.001)] compared with the group with weak CXCR3 levels [RR 1.33 (95 % CI 0.38-4.79, P = 0.65)]. We show here for the first time that CXCL10 and CXCR3 expression are both predictors of favorable outcome in patients treated with tamoxifen.
Breast cancer research and treatment.Breast Cancer Res Treat.2014 May;145(1):73-82. doi: 10.1007/s10549-014-2933-7. Epub 2014 Apr 9.
To investigate the expression levels of CXCL10 and CXCR3 in tumors from breast cancer patients randomized to adjuvant tamoxifen treatment or no endocrine treatment, in order to further study the connection to prognosis and prediction of tamoxifen treatment outcome. Immunohistochemistry on tissue mic
PMID 24715380

Japanese Journal

重症気管支喘息患者への教育・指導が気道炎症にもたらす効果の検討

高久洋太郎,中込一之,西原冬実,小林威仁,杣知行,萩原弘一,金澤實,大田健,永田真
アレルギー 61(2), 194-203, 2012-02-28
… 価した.【結果】患者教育・指導前後でFEV_1やACTスコアに変化はなかったが,AHQスコアは改善した.喀痰中好酸球比率は低下したが,喀痰中好中球比率に変化はなく,関連して好中球走化因子であるIL-8あるいは各種CXCR3リガンド濃度についても変化はなかった.【結語】成人重症喘息患者に対する喘息教育・指導は,喘息患者QOLの改善と気道における好酸球性炎症の抑制には部分的に効果を発揮したが,喘息のコントロール状態と …
NAID 110009425601

Identification of Chemoattractive Factors Involved in the Migration of Bone Marrow-Derived Mesenchymal Stem Cells to Brain Lesions Caused by Prions

Song Chang-Hyun,Honmou Osamu,Furuoka Hidefumi,Horiuchi Motohiro
Journal of Virology 85(21), 11069-11078, 2011-11
… The migration of immortalized human MSCs (hMSCs) was reduced by their pre-treatment with antibodies against the chemokine receptors, CCR3, CCR5, CXCR3 and CXCR4 and by pre-treatment of brain extracts of prion-infected mice with antibodies against the corresponding ligands, suggesting the involvement of these receptors and their ligands in the migration of hMSCs. …
NAID 120004027230

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★リンクテーブル★

リンク元	「ケモカインレセプター」
拡張検索	「CXCR3受容体」「CXCR3レセプター」「CXCR3 receptor」

「ケモカインレセプター」

Chemokine (C-X-C motif) receptor 3
Identifiers
Symbols	CXCR3; CD182; CD183; CKR-L2; CMKAR3; GPR9; IP10-R; Mig-R; MigR
External IDs	OMIM: 300574 MGI: 1277207 HomoloGene: 1153 IUPHAR: CXCR3 ChEMBL: 4441 GeneCards: CXCR3 Gene
Gene Ontology
Molecular function	• chemokine receptor activity; • C-X-C chemokine receptor activity; • chemokine binding;
Cellular component	• cytoplasm; • plasma membrane; • integral to plasma membrane; • external side of plasma membrane;
Biological process	• angiogenesis; • apoptotic process; • cellular component movement; • chemotaxis; • cell adhesion; • elevation of cytosolic calcium ion concentration; • calcium-mediated signaling; • chemokine-mediated signaling pathway;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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