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

Tünde Fekete, G. Koncz, Brigitta Szabo, Andrea Gregus, E. Rajnavolgyi

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 IFNÎ 3 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-A nd 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.

Original languageEnglish
Pages (from-to)380-391
Number of pages12
JournalCellular and Molecular Immunology
Volume14
Issue number4
DOIs
Publication statusPublished - Apr 1 2017

Fingerprint

X-Linked Inhibitor of Apoptosis Protein
Acetylmuramyl-Alanyl-Isoglutamine
Sirolimus
Dendritic Cells
Interferon-gamma
Nucleotides
Cytokines
Phosphatidylinositol 3-Kinase
STAT1 Transcription Factor
NF-kappa B
Cellular Structures
Interleukin-12
HLA Antigens
Mitogen-Activated Protein Kinases
Interleukin-1
Interleukin-10
Cell Wall
Ligation
Interleukin-6
Proteins

Keywords

  • Dendritic cell
  • mTOR
  • NOD2
  • XIAP

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

@article{a01f464ce16a4da6981f8c0d8737cd3e,
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 IFN{\^I} 3 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-A nd 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.",
keywords = "Dendritic cell, mTOR, NOD2, XIAP",
author = "T{\"u}nde Fekete and G. Koncz and Brigitta Szabo and Andrea Gregus and E. Rajnavolgyi",
year = "2017",
month = "4",
day = "1",
doi = "10.1038/cmi.2015.90",
language = "English",
volume = "14",
pages = "380--391",
journal = "Cellular and Molecular Immunology",
issn = "1672-7681",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - 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

AU - Fekete, Tünde

AU - Koncz, G.

AU - Szabo, Brigitta

AU - Gregus, Andrea

AU - Rajnavolgyi, E.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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 IFNÎ 3 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-A nd 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.

AB - 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 IFNÎ 3 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-A nd 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.

KW - Dendritic cell

KW - mTOR

KW - NOD2

KW - XIAP

UR - http://www.scopus.com/inward/record.url?scp=85016749103&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016749103&partnerID=8YFLogxK

U2 - 10.1038/cmi.2015.90

DO - 10.1038/cmi.2015.90

M3 - Article

VL - 14

SP - 380

EP - 391

JO - Cellular and Molecular Immunology

JF - Cellular and Molecular Immunology

SN - 1672-7681

IS - 4

ER -