title: 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.
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.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Tünde
authors.initials: T
authors.lastname: Fekete
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.|Department of Bioengineering, Sapientia Hungarian University of Transylvania, Cluj-Napoca, Romania.
authors.forename: Gabor
authors.initials: G
authors.lastname: Koncz
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Szabo
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gregus
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.|Department of Bioengineering, Sapientia Hungarian University of Transylvania, Cluj-Napoca, Romania.
authors.forename: Eva
authors.initials: E
authors.lastname: Rajnavölgyi
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D018949:Antigens, CD1 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D000119:Acetylmuramyl-Alanyl-Isoglutamine; D018949:Antigens, CD1; D016207:Cytokines; D018836:Inflammation Mediators; D051034:Inhibitor of Apoptosis Proteins; D007371:Interferon-gamma; D015850:Interleukin-6; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; D019869:Phosphatidylinositol 3-Kinases; D050794:STAT1 Transcription Factor; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C429018:NOD2 protein, human; C496866:XIAP protein, human; C546842:MTOR protein, human