CXCL9

Last updated
CXCL9
Identifiers
Aliases CXCL9 , CMK, Humig, MIG, SCYB9, crg-10, C-X-C motif chemokine ligand 9
External IDs OMIM: 601704 HomoloGene: 1813 GeneCards: CXCL9
Orthologs
SpeciesHumanMouse
Entrez

4283

n/a

Ensembl

ENSG00000138755

n/a

UniProt

Q07325

n/a

RefSeq (mRNA)

NM_002416

n/a

RefSeq (protein)

NP_002407

n/a

Location (UCSC) Chr 4: 76 – 76.01 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Chemokine (C-X-C motif) ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation. [3]

Contents

The CXCL9/CXCR3 receptor regulates immune cell migration, differentiation, and activation. Immune reactivity occurs through recruitment of immune cells, such as cytotoxic lymphocytes (CTLs), natural killer (NK) cells, NKT cells, and macrophages. Th1 polarization also activates the immune cells in response to IFN-γ. [4] Tumor-infiltrating lymphocytes are a key for clinical outcomes and prediction of the response to checkpoint inhibitors. [5] In vivo studies suggest the axis plays a tumorigenic role by increasing tumor proliferation and metastasis.[ citation needed ] CXCL9 predominantly mediates lymphocytic infiltration to the focal sites and suppresses tumor growth. [6]

It is closely related to two other CXC chemokines called CXCL10 and CXCL11, whose genes are located near the gene for CXCL9 on human chromosome 4. [7] [8] CXCL9, CXCL10 and CXCL11 all elicit their chemotactic functions by interacting with the chemokine receptor CXCR3. [9]

Biomarkers

CXCL9, -10, -11 have proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the development of adverse cardiac remodeling. [10] [11]

This chemokine has also been associated as a biomarker for diagnosing Q fever infections. [12]

Interactions

CXCL9 has been shown to interact with CXCR3. [13] [14]

CXCL9 in immune reactions

For immune cell differentiation, some reports show that CXCL9 lead to Th1 polarization through CXCR3. [15] In vivo model by Zohar et al. showed that CXCL9, drove increased transcription of T-bet and RORγ, leading to the polarization of Foxp3 − type 1 regulatory (Tr1) cells or T helper 17 (Th17) from naive T cells via STAT1, STAT4, and STAT5 phosphorylation. [15]

Several studies have shown that tumor-associated macrophages (TAMs) play modulatory activities in the TME, and the CXCL9/CXCR3 axis impacts TAMs polarization. The TAMs have opposite effects; M1 for anti-tumor activities, and M2 for pro-tumor activities. Oghumu et al. clarified that CXCR3 deficient mice displayed increased IL-4 production and M2 polarization in a murine breast cancer model, and decreased innate and immune cell-mediated anti-tumor responses. [16]

For immune cell activation, CXCL9 stimulate immune cells through Th1 polarization and activation. Th1 cells produce IFN-γ, TNF-α, IL-2 and enhance anti-tumor immunity by stimulating CTLs, NK cells and macrophages. [17] The IFN-γ-dependent immune activation loop also promotes CXCL9 release. [3]

Immune cells, like Th1, CTLs, NK cells, and NKT cells, show anti-tumor effect against cancer cells through paracrine CXCL9/CXCR3 in tumor models. [6] The autocrine CXCL9/CXCR3 signaling in cancer cells increases cancer cell proliferation, angiogenesis, and metastasis.[ citation needed ]

CXCL9/CXCR3 and the PDL-1/PD-1

The relationship between CXCL9/CXCR3 and the PDL-1/PD-1 is an important area of research. Programmed cell death-1 (PD-1) shows increased expression on T cells at the tumor site compared to T cells present in the peripheral blood, and anti-PD-1 therapy can inhibit “immune escape” and the immune activation. [18] Peng et al. showed that anti-PD-1 could not only enhance T cell-mediated tumor regression but also increase the expression of IFN-γ but not CXCL9 by bone marrow–derived cells. [18] Blockade of the PDL-1/PD-1 axis in T cells may trigger a positive feedback loop at the tumor site through the CXCL9/CXCR3 axis. Also using anti-CTLA4 antibody, this axis was significantly up-regulated in pretreatment melanoma lesions in patients with good clinical response after ipilimumab administration. [19]

CXCL9 and melanoma

CXCL9 has also been identified as candidate biomarker of adoptive T cell transfer therapy in metastatic melanoma. [20] The role of CXCL9/CXCR3 in TME and immune response - this plays a critical role in immune activation through paracrine signaling, impacting efficacy of cancer treatments. [3]

Related Research Articles

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Cell-mediated immunity</span> Immune response that does not involve antibodies

Cellular immunity, also known as cell-mediated immunity, is an immune response that does not rely on the production of antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

<span class="mw-page-title-main">Interleukin 12</span> Interleukin

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

<span class="mw-page-title-main">Interferon gamma</span> InterPro Family

Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.

<span class="mw-page-title-main">Interleukin 29</span> Protein-coding gene in the species Homo sapiens

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

<span class="mw-page-title-main">CCL21</span> Mammalian protein found in Homo sapiens

Chemokine ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine, exodus-2, and secondary lymphoid-tissue chemokine (SLC). CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7. The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.

<span class="mw-page-title-main">CCL17</span> Mammalian protein found in Homo sapiens

CCL17 is a powerful chemokine produced in the thymus and by antigen-presenting cells like dendritic cells, macrophages, and monocytes. CCL17 plays a complex role in cancer. It attracts T-regulatory cells allowing for some cancers to evade an immune response. However, in other cancers, such as melanoma, an increase in CCL17 is linked to an improved outcome. CCL17 has also been linked to autoimmune and allergic diseases.

<span class="mw-page-title-main">CXCL10</span> Mammalian protein found in humans

C-X-C motif chemokine ligand 10 (CXCL10) also known as Interferon gamma-induced protein 10 (IP-10) or small-inducible cytokine B10 is an 8.7 kDa protein that in humans is encoded by the CXCL10 gene. C-X-C motif chemokine 10 is a small cytokine belonging to the CXC chemokine family.

<span class="mw-page-title-main">CXCL11</span> Mammalian protein found in Homo sapiens

C-X-C motif chemokine 11 (CXCL11) is a protein that in humans is encoded by the CXCL11 gene.

<span class="mw-page-title-main">CXCL5</span> Mammalian protein found in Homo sapiens

C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.

CXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins, since they span the cell membrane seven times. There are currently six known CXC chemokine receptors in mammals, named CXCR1 through CXCR6.

<span class="mw-page-title-main">CXCR3</span> Protein-coding gene in humans

Chemokine receptor CXCR3 is a Gαi protein-coupled receptor in the CXC chemokine receptor family. Other names for CXCR3 are G protein-coupled receptor 9 (GPR9) and CD183. There are three isoforms of CXCR3 in humans: CXCR3-A, CXCR3-B and chemokine receptor 3-alternative (CXCR3-alt). CXCR3-A binds to the CXC chemokines CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC) whereas CXCR3-B can also bind to CXCL4 in addition to CXCL9, CXCL10, and CXCL11.

<span class="mw-page-title-main">CXCR5</span> Mammalian protein found in Homo sapiens

C-X-C chemokine receptor type 5 (CXC-R5) also known as CD185 or Burkitt lymphoma receptor 1 (BLR1) is a G protein-coupled seven transmembrane receptor for chemokine CXCL13 and belongs to the CXC chemokine receptor family. It enables T cells to migrate to lymph node and the B cell zones. In humans, the CXC-R5 protein is encoded by the CXCR5 gene.

Understanding of the antitumor immunity role of CD4+ T cells has grown substantially since the late 1990s. CD4+ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.

<span class="mw-page-title-main">Toll-like receptor 4</span> Protein-coding gene in the species Homo sapiens

Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

Immunology is the study of the immune system during health and disease. Below is a list of immunology-related articles.

Immunoediting is a dynamic process that consists of immunosurveillance and tumor progression. It describes the relation between the tumor cells and the immune system. It is made up of three phases: elimination, equilibrium, and escape.

The Immunologic Constant of Rejection (ICR), is a notion introduced by biologists to group a shared set of genes expressed in tissue destructive-pathogenic conditions like cancer and infection, along a diverse set of physiological circumstances of tissue damage or organ failure, including autoimmune disease or allograft rejection. The identification of shared mechanisms and phenotypes by distinct immune pathologies, marked as a hallmarks or biomarkers, aids in the identification of novel treatment options, without necessarily assessing patients phenomenologies individually.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000138755 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 3 Tokunaga R, Zhang W, Naseem M, Puccini A, Berger MD, Soni S, McSkane M, Baba H, Lenz HJ (February 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.
  4. ↑ Schoenborn JR, Wilson CB (2007), Regulation of Interferon-γ During Innate and Adaptive Immune Responses, Advances in Immunology, vol. 96, Elsevier, pp. 41–101, doi:10.1016/s0065-2776(07)96002-2, ISBN   978-0-12-373709-0, PMID   17981204
  5. ↑ 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 (July 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.
  6. 1 2 Gorbachev AV, Kobayashi H, Kudo D, Tannenbaum CS, Finke JH, Shu S, Farber JM, Fairchild RL (2007-02-15). "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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Tensen CP, Flier J, Van Der Raaij-Helmer EM, Sampat-Sardjoepersad S, Van Der Schors RC, Leurs R, Scheper RJ, Boorsma DM, Willemze R (May 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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 (June 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.
  14. ↑ Weng Y, Siciliano SJ, Waldburger KE, Sirotina-Meisher A, Staruch MJ, Daugherty BL, Gould SL, Springer MS, DeMartino JA (July 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.
  15. 1 2 Zohar Y, Wildbaum G, Novak R, Salzman AL, Thelen M, Alon R, Barsheshet Y, Karp CL, Karin N (May 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.
  16. ↑ Oghumu S, Varikuti S, Terrazas C, Kotov D, Nasser MW, Powell CA, Ganju RK, Satoskar AR (September 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.
  17. ↑ Mosser DM, Edwards JP (December 2008). "Exploring the full spectrum of macrophage activation". Nature Reviews. Immunology. 8 (12): 958–69. doi:10.1038/nri2448. PMC   2724991 . PMID   19029990.
  18. 1 2 Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizée G, Radvanyi L, Hwu P (October 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.
  19. ↑ 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 (July 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.
  20. ↑ 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 (October 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.

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