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Interferon gamma boosts the nucleotide oligomerization domain 2-mediated signaling pathway in human dendritic cells in an X-linked inhibitor of apoptosis protein and mammalian target of rapamycin-dependent manner

Cellular & Molecular Immunology volume 14, pages 380–391 (2017)Cite this article

Abstract

The cytoplasmic nucleotide oligomerization domain 2 (NOD2) receptor recognizes the bacterial cell wall component muramyl dipeptide (MDP). NOD2 ligation initiates the nuclear factor kappa B and the mitogen-activated protein kinase cascades. However, administering MDP alone is insufficient to elicit strong cytokine responses in various immune cells, including dendritic cells (DCs). Because the simultaneous presence of various microbial products and cytokines in inflamed tissues modulates DC function, we initiated this study to examine how interferon gamma (IFNγ), a central modulator of inflammation, affects the NOD2-mediated signaling pathway in human conventional DCs (cDCs). Synergistic stimulation of DCs with MDP and IFNγ increased the expression of CD40, CD80, CD83, CD86, and human leukocyte antigen DQ proteins and significantly elevated the production of pro-inflammatory cytokines IL-1β, IL-6, IL-12, and tumour necrosis factor (TNF), as well as anti-inflammatory cytokine IL-10. Furthermore, the simultaneous presence of MDP and IFNγ was necessary to decrease IkBα protein levels. By investigating various mechanisms implicated in MDP- and IFNγ-mediated signaling pathways, we revealed that the increased production of pro-inflammatory cytokines is highly dependent on the X-linked inhibitor of apoptosis protein (XIAP) but not on cellular IAP1 and IAP2. We also found that the NOD2 signaling pathway is regulated by the mammalian target of rapamycin (mTOR) but is not affected by phosphatidylinositol-3 kinase or signal transducer and activator of transcription 1 inhibition. Our results demonstrate, for the first time, that IFNγ positively affects NOD2-mediated signaling in human cDCs, in a manner considerably dependent on XIAP and partially dependent on mTOR.

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References

  1. Strober W, Murray PJ, Kitani A, Watanabe T . Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 2006; 6: 9–20.

    Article  CAS  PubMed  Google Scholar 

  2. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH et al. Activation of innate immune antiviral responses by Nod2. Nat Immunol 2009; 10: 1073–1080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vandenabeele P, Bertrand MJ . The role of the IAP E3 ubiquitin ligases in regulating pattern-recognition receptor signalling. Nat Rev Immunol 2012; 12: 833–844.

    Article  CAS  PubMed  Google Scholar 

  4. Bertrand MJ, Doiron K, Labbe K, Korneluk RG, Barker PA, Saleh M . Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 2009; 30: 789–801.

    Article  CAS  PubMed  Google Scholar 

  5. Damgaard RB, Nachbur U, Yabal M, Wong WW, Fiil BK, Kastirr M et al. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell 2012; 46: 746–758.

    Article  CAS  PubMed  Google Scholar 

  6. Ghorpade DS, Kaveri SV, Bayry J, Balaji KN . Cooperative regulation of NOTCH1 protein-phosphatidylinositol 3-kinase (PI3K) signaling by NOD1, NOD2, and TLR2 receptors renders enhanced refractoriness to transforming growth factor-beta (TGF-beta)- or cytotoxic T-lymphocyte antigen 4 (CTLA-4)-mediated impairment of human dendritic cell maturation. J Biol Chem 2011; 286: 31347–31360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kaur S, Uddin S, Platanias LC . The PI3′ kinase pathway in interferon signaling. J Interferon Cytokine Res 2005; 25: 780–787.

    Article  CAS  PubMed  Google Scholar 

  8. Platanias LC . Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 2005; 5: 375–386.

    Article  CAS  PubMed  Google Scholar 

  9. Fujimura T, Yamasaki K, Hidaka T, Ito Y, Aiba S . A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18) and IFN-beta synergistically induce dendritic cell maturation with augmented IL-12 production and suppress melanoma growth. J Dermatol Sci 2011; 62: 107–115.

    Article  CAS  PubMed  Google Scholar 

  10. Rosenzweig HL, Kawaguchi T, Martin TM, Planck SR, Davey MP, Rosenbaum JT . Nucleotide oligomerization domain-2 (NOD2)-induced uveitis: dependence on IFN-gamma. Invest Ophthalmol Vis Sci 2009; 50: 1739–1745.

    Article  PubMed  Google Scholar 

  11. Totemeyer S, Sheppard M, Lloyd A, Roper D, Dowson C, Underhill D et al. IFN-gamma enhances production of nitric oxide from macrophages via a mechanism that depends on nucleotide oligomerization domain-2. J Immunol 2006; 176: 4804–4810.

    Article  PubMed  Google Scholar 

  12. Saiki I, Sone S, Fogler WE, Kleinerman ES, Lopez-Berestein G, Fidler IJ . Synergism between human recombinant gamma-interferon and muramyl dipeptide encapsulated in liposomes for activation of antitumor properties in human blood monocytes. Cancer Res 1985; 45: 6188–6193.

    CAS  PubMed  Google Scholar 

  13. Nguyen H, Ramana CV, Bayes J, Stark GR . Roles of phosphatidylinositol 3-kinase in interferon-gamma-dependent phosphorylation of STAT1 on serine 727 and activation of gene expression. J Biol Chem 2001; 276: 33361–33368.

    Article  CAS  PubMed  Google Scholar 

  14. Lekmine F, Sassano A, Uddin S, Smith J, Majchrzak B, Brachmann SM et al. Interferon-gamma engages the p70 S6 kinase to regulate phosphorylation of the 40S S6 ribosomal protein. Exp Cell Res 2004; 295: 173–182.

    Article  CAS  PubMed  Google Scholar 

  15. Gough DJ, Sabapathy K, Ko EY, Arthur HA, Schreiber RD, Trapani JA et al. A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon gamma response genes. J Biol Chem 2007; 282: 938–946.

    Article  CAS  PubMed  Google Scholar 

  16. Ramana CV, Gil MP, Schreiber RD, Stark GR . Stat1-dependent and -independent pathways in IFN-gamma-dependent signaling. Trends Immunol 2002; 23: 96–101.

    Article  CAS  PubMed  Google Scholar 

  17. Fritz JH, Girardin SE, Fitting C, Werts C, Mengin-Lecreulx D, Caroff M et al. Synergistic stimulation of human monocytes and dendritic cells by toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur J Immunol 2005; 35: 2459–2470.

    Article  CAS  PubMed  Google Scholar 

  18. Merad M, Sathe P, Helft J, Miller J, Mortha A . The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Ann Rev Immunol 2013; 31: 563–604.

    Article  CAS  Google Scholar 

  19. Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M et al. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 1999; 189: 1839–1845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Windheim M, Lang C, Peggie M, Plater LA, Cohen P . Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. Biochem J 2007; 404: 179–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lopez J, Meier P . To fight or die - inhibitor of apoptosis proteins at the crossroad of innate immunity and death. Curr Opin Cell Biol 2010; 22: 872–881.

    Article  CAS  PubMed  Google Scholar 

  22. Soliman GA . The role of mechanistic target of rapamycin (mTOR) complexes signaling in the immune responses. Nutrients 2013; 5: 2231–2257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schreibelt G, Tel J, Sliepen KH, Benitez-Ribas D, Figdor CG, Adema GJ et al. Toll-like receptor expression and function in human dendritic cell subsets: implications for dendritic cell-based anti-cancer immunotherapy. Cancer Immunol Immunother 2010; 59: 1573–1582.

    Article  CAS  PubMed  Google Scholar 

  24. Vuckovic S, Clark GJ, Hart DN . Growth factors, cytokines and dendritic cell development. Curr Pharm Des 2002; 8: 405–418.

    Article  CAS  PubMed  Google Scholar 

  25. Tada H, Aiba S, Shibata K, Ohteki T, Takada H . Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun 2005; 73: 7967–7976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Uehori J, Fukase K, Akazawa T, Uematsu S, Akira S, Funami K et al. Dendritic cell maturation induced by muramyl dipeptide (MDP) derivatives: monoacylated MDP confers TLR2/TLR4 activation. J Immunol 2005; 174: 7096–7103.

    Article  CAS  PubMed  Google Scholar 

  27. He T, Tang C, Xu S, Moyana T, Xiang J . Interferon gamma stimulates cellular maturation of dendritic cell line DC2.4 leading to induction of efficient cytotoxic T cell responses and antitumor immunity. Cell Mol Immunol 2007; 4: 105–111.

    CAS  PubMed  Google Scholar 

  28. Delneste Y, Charbonnier P, Herbault N, Magistrelli G, Caron G, Bonnefoy JY et al. Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages. Blood 2003; 101: 143–150.

    Article  CAS  PubMed  Google Scholar 

  29. Frasca L, Nasso M, Spensieri F, Fedele G, Palazzo R, Malavasi F et al. IFN-gamma arms human dendritic cells to perform multiple effector functions. J Immunol 2008; 180: 1471–1481.

    Article  CAS  PubMed  Google Scholar 

  30. Schroder K, Sweet MJ, Hume DA . Signal integration between IFNgamma and TLR signalling pathways in macrophages. Immunobiology 2006; 211: 511–524.

    CAS  PubMed  Google Scholar 

  31. Benlahrech A, Duraisingham S, King D, Verhagen L, Rozis G, Amjadi P et al. Human blood CD1c dendritic cells stimulate IL-12-independent IFN-gamma responses and have a strikingly low inflammatory profile. J Leukoc Biol 2015; 97: 873–885.

    Article  CAS  PubMed  Google Scholar 

  32. Greter M, Helft J, Chow A, Hashimoto D, Mortha A, Agudo-Cantero J et al. GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 2012; 36: 1031–1046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Danis VA, Franic GM, Rathjen DA, Brooks PM . Effects of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-2, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and IL-6 on the production of immunoreactive IL-1 and TNF-alpha by human monocytes. Clin Exp Immunol 1991; 85: 143–150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kassianos AJ, Hardy MY, Ju X, Vijayan D, Ding Y, Vulink AJ et al. Human CD1c (BDCA-1)+ myeloid dendritic cells secrete IL-10 and display an immuno-regulatory phenotype and function in response to Escherichia coli. Eur J Immunol 2012; 42: 1512–1522.

    Article  CAS  PubMed  Google Scholar 

  35. Haidinger M, Poglitsch M, Geyeregger R, Kasturi S, Zeyda M, Zlabinger GJ et al. A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation. J Immunol 2010; 185: 3919–3931.

    Article  CAS  PubMed  Google Scholar 

  36. Fekete T, Pazmandi K, Szabo A, Bacsi A, Koncz G, Rajnavolgyi E . The antiviral immune response in human conventional dendritic cells is controlled by the mammalian target of rapamycin. J Leukoc Biol 2014; 96: 579–589.

    Article  PubMed  Google Scholar 

  37. Risco A, Cuenda A . New insights into the p38gamma and p38delta MAPK Pathways. J Signal Transduct 2012; 2012: 520289.

    Article  PubMed  Google Scholar 

  38. Llanos S, Cuadrado A, Serrano M . MSK2 inhibits p53 activity in the absence of stress. Sci Signal 2009; 2: ra57.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Matsunaga T, Ishida T, Takekawa M, Nishimura S, Adachi M, Imai K . Analysis of gene expression during maturation of immature dendritic cells derived from peripheral blood monocytes. Scand J Immunol 2002; 56: 593–601.

    Article  CAS  PubMed  Google Scholar 

  40. Muller-Sienerth N, Dietz L, Holtz P, Kapp M, Grigoleit GU, Schmuck C et al. SMAC mimetic BV6 induces cell death in monocytes and maturation of monocyte-derived dendritic cells. PLoS One 2011; 6: e21556.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Yang S, Wang B, Humphries F, Jackson R, Healy ME, Bergin R et al. Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis. Nat Immunol 2013; 14: 927–936.

    Article  CAS  PubMed  Google Scholar 

  42. Luu K, Greenhill CJ, Majoros A, Decker T, Jenkins BJ, Mansell A . STAT1 plays a role in TLR signal transduction and inflammatory responses. Immunol Cell Biol 2014; 92: 761–769.

    Article  CAS  PubMed  Google Scholar 

  43. Hedl M, Abraham C . Secretory mediators regulate Nod2-induced tolerance in human macrophages. Gastroenterology 2011; 140: 231–241.

    Article  CAS  PubMed  Google Scholar 

  44. Rosborough BR, Raich-Regue D, Matta BM, Lee K, Gan B, DePinho RA et al. Murine dendritic cell rapamycin-resistant and rictor-independent mTOR controls IL-10, B7-H1, and regulatory T-cell induction. Blood 2013; 121: 3619–3630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schmitz F, Heit A, Dreher S, Eisenacher K, Mages J, Haas T et al. Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur J Immunol 2008; 38: 2981–2992.

    Article  CAS  PubMed  Google Scholar 

  46. Makarevic J, Tawanaie N, Juengel E, Reiter M, Mani J, Tsaur I et al. Cross-communication between histone H3 and H4 acetylation and Akt-mTOR signalling in prostate cancer cells. J Cell Mol Med 2014; 18: 1460–1466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A . T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol 2002; 3: 643–651.

    Article  CAS  PubMed  Google Scholar 

  48. Tsaprouni LG, Ito K, Powell JJ, Adcock IM, Punchard N . Differential patterns of histone acetylation in inflammatory bowel diseases. J Inflamm (Lond) 2011; 8: 1.

    Article  CAS  Google Scholar 

  49. Hu X, Ivashkiv LB . Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity 2009; 31: 539–550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ellouz F, Adam A, Ciorbaru R, Lederer E . Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun 1974; 59: 1317–1325.

    Article  CAS  PubMed  Google Scholar 

  51. Ogawa C, Liu YJ, Kobayashi KS . Muramyl dipeptide and its derivatives: peptide adjuvant in immunological disorders and cancer therapy. Curr Bioact Compd 2011; 7: 180–197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Hungarian Scientific Research Grants OTKA NN114423 and the Romanian Ministry of Education, Executive Agency For Higher Education, Research, Development and Innovation Funding, PNCDI II, project no. 119/2014. Supplementary information of this article can be found on the Cellular & Molecular Immunology’s website (http://www.nature.com/cmi)

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Authors and Affiliations

  1. Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Tünde Fekete, Gabor Koncz, Brigitta Szabo, Andrea Gregus & Eva Rajnavölgyi

  2. Department of Bioengineering, Sapientia Hungarian University of Transylvania, Cluj-Napoca, Romania

    Gabor Koncz & Eva Rajnavölgyi

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Correspondence to Eva Rajnavölgyi.

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Supplementary information of this article can be found on the Cellular & Molecular Immunology’s website (http://www.nature.com/cmi).

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Fekete, T., Koncz, G., Szabo, B. et al. Interferon gamma boosts the nucleotide oligomerization domain 2-mediated signaling pathway in human dendritic cells in an X-linked inhibitor of apoptosis protein and mammalian target of rapamycin-dependent manner. Cell Mol Immunol 14, 380–391 (2017). https://doi.org/10.1038/cmi.2015.90

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