Abstract
The aims of this study are to examine the effect of sphingosine 1-phosphate (S1P) on IL-2-activated natural killer (NK) cell lysis of K562 tumor cells and immature dendritic cells (iDCs), and to investigate the mechanisms involved in S1P activity. Our results show that S1P protected K562 cells or iDCs from NK cell lysis, which was reversed by FTY720 and SEW2871, the antagonists of S1P1. S1P did not modulate the expression of NKG2D, NKp30, NKp44 or CD158 on the surface of NK cells, and neither affected the expression of CD80, CD83, or CD86 on the surface of DCs. In contrast, it increased the expression of HLA-I and HLA-E on DCs, an activity that was inhibited by FTY720 or SEW2871. Similarly, the inhibitory effect of S1P for NK cell lysis of K562 cells was directed toward S1P1 expressed on the tumor cells but not on NK cells. Further analysis indicates that NK cells secreted various cytokines and chemokines with various intensities: (1) low (IL-4, IL-6, IL-12, TNF-α and MCP-1); (2) intermediate (IL-1β, IL-10, TGF-β1, and IL-17A); (3) high (IFN-γ, and MIP-1α); and (4) very high (MIP-1β). S1P significantly reduced the release of IL-17A and IFN-γ from NK cells, but this inhibition was S1P1-independent. These results indicate that S1P is an anti-inflammatory molecule, and that S1P1 is important for the interaction among NK cells and tumor cells or DCs leading to up-regulation of HLA-I and HLA-E on the surface of DCs, but not in S1P inhibition of the release of inflammatory cytokines from NK cells. Further, the results suggest that FTY720 and SEW2871 may potentially be used as prophylactic and/or therapeutic drugs to treat cancer patients.
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Naumova E, Mihaylova A, Ivanova M, Mihailova S (2007) Impact of KIR/HLA ligand combinations on immune responses in malignant melanoma. Cancer Immunol Immunother 56:95–100
Steinman RM, Inaba K (1998) Myeloid dendritic cells. J Leukoc Biol 66:205–208
Gauzzi MC, Purificato C, Donato K, Jin Y, Wang L, Daniel KC, Maghazachi AA, Belardelli F, Adorini L, Gessani S (2005) Suppressive effect of 1 alpha, 25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: impairment of functional activities and chemotaxis. J Immunol 174:270–276
Hla T, Venkataraman K, Michaud J (2008) The vascular S1P gradient—cellular sources and biological significance. Biochim Biophys Acta 1781:477–482
Cinque B, Di Marzio L, Centi C, Di Rocco C, Riccardi C, Cifone MG (2003) Sphingolipids and the immune system. Pharmacol Res 47:421–437
Chun J, Goetzl EJ, Hla T, Igarashi Y, Lynch KR, Moolenaar W, Pyne, Tigyi G (2002) International union of pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol Rev 54:265–269
Brinkmann V (2007) Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 115:84–105
Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296:346–349
Coste O, Pierre S, Marian C, Brenneis C, Angioni C, Schmidt H, Popp L, Geisslinger G, Scholich K (2008) Antinociceptive activity of the S1P-receptor agonist FTY720. J Cell Mol Med 12:995–1004
Sanna MG, Liao J, Jo E, Alfonso C, Ahn M-Y, Peterson MS, Webb B, Lefebvre S, Chun J, Gray N, Rosen H (2004) Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 279:13839–13848
Maeda Y, Matsuyuki H, Shimano K, Kataoka H, Sugahara K, Chiba K (2007) Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3. J Immunol 178:3437–3446
Lan YY, De Creus A, Colvin BL, Abe M, Brinkmann V, Coates P, Thomson AW (2005) The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo. Am J Transplant 5:2649–2659
Vaessen LM, van Besouw NM, Mol WM, Ijzermans JN, Weimar W (2006) FTY720 treatment of kidney transplant patients: a differential effect on B cells, naïve T cells, memory T cells and NK cells. Transplant Immunol 15:281–288
Mayer K, Birnbaum F, Reinhard T, Braunstein S, Claas F, Sundmacher R (2004) FTY720 prolongs clear corneal allograft survival with a differential effect on different lymphocyte populations. Br J Ophthalmol 88:915–919
Lagadari M, Lehmann K, Ziemer M, Truta-Feles K, Berod L, Idzko M, Barz D, Kamradt T, Maghazachi AA, Norgauer J (2009) Sphingosine-1-phosphate inhibits the cytotoxic activity of NK cells via Gs protein-mediated signaling. Int J Oncol 34:287–288
Moretta A (2002) Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2:957–964
Sand KL, Knudsen E, Rolin J, Al-Falahi Y, Maghazachi AA (2009) Modulation of natural killer cell cytotoxicity and cytokine release by the drug glatiramer acetate. Cell Mol Life Sci 66:1446–1456
Kveberg L, Bryceson Y, Inngjerdingen M, Rolstad B, Maghazachi AA (2002) Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases. Eur J Immunol 32:1856–1864
Oz-Arslan D, Rüscher W, Myrtek D, Ziemer M, Jin Y, Damaj BB, Sorichter S, Idzko M, Norgauer J, Maghazachi AA (2006) IL-6 and IL-8 release is mediated via multiple signaling pathways after stimulating dendritic cells with lysophospholipids. J Leukoc Biol 80:287–297
Panther E, Idzko M, Corinti S, Ferrari D, Herouy Y, Mockenhaupt M, Dichmann S, Gebicke-Haerter P, Di Virgilio F, Girolomoni G, Norgauer J (2002) The influence of lysophosphatidic acid on the functions of human dendritic cells. J Immunol 169:4129–4135
Jin Y, Knudsen E, Wang L, Bryceson Y, Damaj B, Gessani S, Maghazachi AA (2003) Sphingosine 1-phosphate is a novel inhibitor of T cell proliferation. Blood 101:4909–4915
Damaj BB, Becerra CB, Esber HJ, Wen Y, Maghazachi AA (2007) Functional expression of H4 histamine receptor in human natural killer cells, monocytes, and dendritic cells. J Immunol 179:7907–7915
Sekiguchi M, Iwasaki T, Kitano M, Kuno H, Hashimoto N, Kawahito Y, Azuma M, Hla T, Sano H (2008) Role of sphingosine 1-phosphate in the pathogenesis of Sjogren’s syndrome. J Immunol 180:1921–1928
Lagadari M, Truta-Feles K, Lehman K, Berod L, Ziemer M, Idzko M, Barz D, Kamradt T, Maghazachi AA, Norgauer J (2009) Lysophosphatidic acid inhibits the cytotoxic activity of NK cells: involvement of Gs protein-mediated signalling. Int Immunol 21:667–677
Dorsam G, Graeler MH, Seroogy C, Kong Y, Voice JK, Goetzl EJ (2003) Transduction of multiple effects of sphingosine 1-phosphate (S1P) on T cell functions by the S1P1 G protein-coupled receptor. J Immunol 171:3500–3507
Müller H, Hofer S, Kaneider N, Neuwirt H, Mosheimer B, Mayer G, Konwalinka G, Heufler C, Tiefenthaler M (2005) The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells. Eur J Immunol 35:533–545
Dudek SM, Camp SM, Chiang ET, Singleton PA, Usatyuk PV, Zhao Y, Natarajan V, Garcia JGN (2007) Pulmonary endothelial cell barrier enhancement by FTY720 does not require the S1P1 receptor. Cell Signal 19:1754–1764
Paugh SW, Cassidy MP, He H, Milstien S, Sim-Selley LJ, Spiegel S, Selley DE (2006) Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor. Mol Pharmacol 70:41–50
Long EO, Barber DF, Burshtyn DN, Faure M, Peterson M, Rajagopalan S, Renard V, Sandusky M, Stebbins CC, Wagtmann N, Watzl C (2001) Inhibition of natural killer cell activation signals by killer cell immunoglobulin-like receptors (CD158). Immuno Rev 181:223–233
Lee N, Llano M, Carretero M, Ishitani A, Navarro F, López-Botet M, Geraghty DE (1998) HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc Natl Acad Sci USA 95:5199–5204
Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S (2008) The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation. Int Immunol 20:1361–1368
Kleinschek MA, Boniface K, Sadekova S, Grein J, Murphy EE, Turner SP, Raskin L, Desai B, Faubion WA, del Waal Malefyt R, Pierce RH, McClanahan T, Kastelein RA (2009) Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med 206:525–534
Cosmi L, De Palma R, Santarlasci V, Maggi L, Capone M, Frosali F, Rodolico G, Querci V, Abbate G, Angeli R, Berrino L, Fambrini M, Caproni M, Tonelli F, Lazzeri E, Parronchi P, Liotta F, Maggi E, Romagnani S, Annunziato F (2008) Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med 205:1903–1916
Walzer T, Chiossone L, Chaix J, Calver A, Carozzo C, Garrigue-Antar L, Jacques Y, Baratin M, Tomasello E, Vivier E (2007) Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat Immunol 12:1337–1344
Acknowledgments
We would like to thank Dr. Volker Brinkmann (Novartis Pharma AG, Basel, Switzerland) for the generous gift of FTY720. This work was supported by grants from Anders Jahres Fond, the University of Oslo and the Norwegian Cancer Society. Johannes Rolin is supported by Forskerlinjen from the Faculty of Medicine at the University of Oslo.
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Rolin, J., Sand, K.L., Knudsen, E. et al. FTY720 and SEW2871 reverse the inhibitory effect of S1P on natural killer cell mediated lysis of K562 tumor cells and dendritic cells but not on cytokine release. Cancer Immunol Immunother 59, 575–586 (2010). https://doi.org/10.1007/s00262-009-0775-7
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DOI: https://doi.org/10.1007/s00262-009-0775-7