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IP-10 and fractalkine induce cytotoxic phenotype of murine NK cells

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Abstract

We characterized the murine NK cell subsets of the tumor microenvironment (TME) with low expressions of CD16 and NKG2D and investigated the chemokines that deter CD16low NKG2Dlow subsets. Our results demonstrated the activation of primary and KY-1 NK cell by ligands and found that exogenous CXCL10/interferon-gamma-induced protein 10 (IP-10) and fractalkine (FKN) can up-regulate the expression of CD16 and NKG2D. Moreover, both IP-10 and FKN are shown to facilitate migration, adhesion and cytotoxicity of NK cell subsets of the TME, due to the up-regulated CD16 and NKG2D. Overall, our data provide a new path by which to enhance murine NK cell cytotoxic potential and improve the quality of NK cells of the TME.

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References

  1. Vujanovic L, Ballard W, Thorne SH et al (2012) Adenovirus-engineered human dendritic cells induce natural killer cell chemotaxis via CXCL8/IL-8 and CXCL10/IP-10. Oncoimmunology 1:448–457

    Article  Google Scholar 

  2. Sarkar S, Germerad WTV, Rouschop KMA et al (2013) Hypoxia induced impairment of NK cell cytotoxicity against multiple myeloma can be overcome by IL-2 activation of the NK cells. PLoS ONE 8:e64835

    Article  Google Scholar 

  3. Yoneda O, Imai T, Nishimura M et al (2003) Membrane-bound form of fractalkine induces IFN-gamma production by NK cells. Eur J Immunol 33:53–58

    Article  Google Scholar 

  4. Zeng Y, Huebener N, Fest S et al (2007) Fractalkine (CX3CL1)- and interleukin-2-enriched neuroblastoma microenvironment induces eradication of metastases mediated by T cells and natural killer cells. Cancer Res 67:2331–2338

    Article  Google Scholar 

  5. Luster AD, Leder P (1993) IP-10, a –C–X–C– chemokine, elicits a potent thymus-dependent antitumor response in vivo. J Exp Med 178:1057–1065

    Article  Google Scholar 

  6. Moriai S, Takahara M, Ogino T et al (2009) Production of interferon-{gamma}-inducible protein-10 and its role as an autocrine invasion factor in nasal natural killer/T-cell lymphoma cells. Clin Cancer Res 15:6771–6779

    Article  Google Scholar 

  7. Di Santo JP (2008) Natural killer cells: diversity in search of a niche. Nat Immunol 9:473–475

    Article  Google Scholar 

  8. Huntington ND, Vosshenrich CA, Di Santo JP (2007) Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat Rev Immunol 7:703–714

    Article  Google Scholar 

  9. Walzer T, Vivier E (2006) NK cell development: gas matters. Nat Immunol 7:702–704

    Article  Google Scholar 

  10. Todorova D, Sabatier F, Doria E et al (2011) Fractalkine expression induces endothelial progenitor cell lysis by natural killer cells. PLoS ONE 6:e26663

    Article  Google Scholar 

  11. Friese MA, Wischhusen J, Wick W et al (2004) RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res 64:7596–7603

    Article  Google Scholar 

  12. Lehmann D, Spanholtz J, Osl M et al (2012) Ex vivo generated natural killer cells acquire typical natural killer receptors and display a cytotoxic gene expression profile similar to peripheral blood natural killer cells. Stem Cells Dev 21:2926–2938

    Article  Google Scholar 

  13. Fujimura S, Takahashi H, Yuda K et al (2012) Angiostatic effect of CXCR3 expressed on choroidal neovascularization. Invest Ophthalmol Vis Sci 53:1999–2006

    Article  Google Scholar 

  14. Dufour JH, Dziejman M, Liu MT et al (2002) IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking. J Immunol 168:3195–3204

    Article  Google Scholar 

  15. Kim HY, Kim S, Chung DH (2006) FcgammaRIII engagement provides activating signals to NKT cells in antibody-induced joint inflammation. J Clin Invest 116:2484–2492

    Article  Google Scholar 

  16. Yamin R, Kaynan NS, Glasner A et al (2013) The viral KSHV chemokine vMIP-II inhibits the migration of Naive and activated human NK cells by antagonizing two distinct chemokine receptors. PLoS Pathog 9:e1003568

    Article  Google Scholar 

  17. Yang XL, Chu YW, Wang Y et al (2006) Targeted in vivo expression of IFN-gamma-inducible protein 10 induces specific antitumor activity. J Leukoc Biol 80:1434–1444

    Article  Google Scholar 

  18. Kuo CH, Liu CJ, Lu CY et al (2014) 17beta-estradiol inhibits mesenchymal stem cells-induced human AGS gastric cancer cell mobility via suppression of CCL5- Src/Cas/Paxillin signaling pathway. Int J Med Sci 11:7–16

    Article  Google Scholar 

  19. Aldinucci D, Colombatti A (2014) The inflammatory chemokine CCL5 and cancer progression. Mediators Inflamm 2014:292376

    Article  Google Scholar 

  20. Wang S, Zhou M, Lin F et al (2014) Interferon-gamma induces senescence in normal human melanocytes. PLoS ONE 9:e93232

    Article  Google Scholar 

  21. Rupertus K, Sinistra J, Scheuer C et al (2014) Interaction of the chemokines I-TAC (CXCL11) and SDF-1 (CXCL12) in the regulation of tumor angiogenesis of colorectal cancer. Clin Exp Metastasis 31:447–459

    Article  Google Scholar 

  22. Walter HL, van der Maten G, Antunes AR et al (2015) Treatment with AMD3100 attenuates the microglial response and improves outcome after experimental stroke. J Neuroinflammation 12:24

    Article  Google Scholar 

  23. Markowitz GJ, Michelotti GA, Diehl AM et al (2015) Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma. Sci Bull 60:762–772

    Article  Google Scholar 

  24. Jinquan T, Quan S, Jacobi HH et al (2000) CXC chemokine receptor 3 expression on CD34(+) hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor: chemotaxis and adhesion induced by its ligands, interferon gamma-inducible protein 10 and monokine induced by interferon gamma. Blood 96:1230–1238

    Google Scholar 

  25. Arenberg DA, White ES, Burdick MD et al (2001) Improved survival in tumor-bearing SCID mice treated with interferon-gamma-inducible protein 10 (IP-10/CXCL10). Cancer Immunol Immunother 50:533–538

    Article  Google Scholar 

  26. Zhang Y, Gao Z, Wang D et al (2014) Accumulation of natural killer cells in ischemic brain tissues and the chemotactic effect of IP-10. J Neuroinflammation 11:79

    Article  Google Scholar 

  27. Li G, Tian L, Hou JM et al (2005) Improved therapeutic effectiveness by combining recombinant CXC chemokine ligand 10 with Cisplatin in solid tumors. Clin Cancer Res 11:4217–4224

    Article  Google Scholar 

  28. Yu YR, Fong AM, Combadiere C et al (2007) Defective antitumor responses in CX3CR1-deficient mice. Int J Cancer 121:316–322

    Article  Google Scholar 

  29. Guo J, Chen T, Wang B et al (2003) Chemoattraction, adhesion and activation of natural killer cells are involved in the antitumor immune response induced by fractalkine/CX3CL1. Immunol Lett 89:1–7

    Article  Google Scholar 

  30. Umehara H, Bloom ET, Okazaki T et al (2001) Fractalkine and vascular injury. Trends Immunol 22:602–607

    Article  Google Scholar 

  31. Lockwood CJ, Huang SJ, Chen CP et al (2013) Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia. Am J Pathol 183:841–856

    Article  Google Scholar 

  32. Tardaguila M, Mira E, García-Cabezas MA et al (2013) CX3CL1 promotes breast cancer via transactivation of the EGF pathway. Cancer Res 73:4461–4473

    Article  Google Scholar 

  33. Liu M, Guo S, Stiles JK et al (2011) The emerging role of CXCL10 in cancer. Oncol Lett 2:583–589

    Google Scholar 

  34. Liu K, Zhang WW, Liu L et al (2009) Ghrelin inhibits apoptosis induced by high glucose and sodium palmitate in adult rat cardiomyocytes through the PI3 K-Akt signaling pathway. Regul Pept 155:62–69

    Article  Google Scholar 

  35. Tseng CK, Lin CK, Chang HW et al (2014) Aqueous extract of Gracilaria tenuistipitata suppresses LPS-induced NF-kappaB and MAPK activation in RAW 264.7 and rat peritoneal macrophages and exerts hepatoprotective effects on carbon tetrachloride-treated rat. PLoS ONE 9:e86557

    Article  Google Scholar 

  36. O’Connor TP, Liesen DA, Mann PC et al (2002) A high isoflavone soy protein diet and intravenous genistein delay rejection of rat cardiac allografts. J Nutr 132:2283–2287

    Google Scholar 

  37. Kakuta Y, Okumi M, Miyagawa S et al (2012) Blocking of CCR5 and CXCR3 suppresses the infiltration of macrophages in acute renal allograft rejection. Transplantation 93:24–31

    Article  Google Scholar 

  38. Tsutahara K, Okumi M, Kakuta Y et al (2012) The blocking of CXCR3 and CCR5 suppresses the infiltration of T lymphocytes in rat renal ischemia reperfusion. Nephrol Dial Transplant 27:3799–3806

    Article  Google Scholar 

  39. Jin HJ, Wang N, Wang C et al (2014) MicroRNAs in hypoxia and acidic tumor microenvironment. Chin Sci Bull 59:2223–2231

    Article  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81171975) and the Tianjin Institutes for Basic Sciences (15JCYBJC26900). We would like to thank Mr. Jie Zhang for his assistance in flow cytometric analysis.

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Correspondence to Yue Wang.

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The authors declare that they have no conflict of interest.

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Fang Liu and Junfang Qin contributed equally to this work.

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Liu, F., Qin, J., Zhang, H. et al. IP-10 and fractalkine induce cytotoxic phenotype of murine NK cells. Sci. Bull. 61, 202–211 (2016). https://doi.org/10.1007/s11434-015-0961-2

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  • DOI: https://doi.org/10.1007/s11434-015-0961-2

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