PMID- 28256612
OWN - NLM
STAT- MEDLINE
DCOM- 20181101
LR  - 20231213
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
DP  - 2017 Mar 3
TI  - The role of indoleamine 2,3-dioxygenase-aryl hydrocarbon receptor pathway in the 
      TLR4-induced tolerogenic phenotype in human DCs.
PG  - 43337
LID - 10.1038/srep43337 [doi]
LID - 43337
AB  - A controlled inflammatory response is required for protection against infection, 
      but persistent inflammation causes tissue damage. Dendritic cells (DCs) have a 
      unique capacity to promote both inflammatory and anti-inflammatory processes. One 
      key mechanism involved in DC-mediated immunosuppression is the expression of 
      tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO has been 
      implicated in diverse processes in health and disease but its role in endotoxin 
      tolerance in human DCs is still controversial. Here we investigated the role of 
      IDO in shaping DCs phenotype and function under endotoxin tolerance conditions. 
      Our data show that TLR4 ligation in LPS-primed DCs, induced higher levels of both 
      IDO isoforms together with the transcription factor aryl-hydrocarbon receptor 
      (AhR), compared to unprimed controls. Additionally, LPS conditioning induced an 
      anti-inflammatory phenotype in DCs - with an increase in IL-10 and higher 
      expression of programmed death ligand (PD-L)1 and PD-L2 - which were partially 
      dependent on IDO. Furthermore, we demonstrated that the AhR-IDO pathway was 
      responsible for the preferential activation of non-canonical NF-kappaB pathway in 
      LPS-conditioned DCs. These data provide new insight into the mechanisms of the 
      TLR4-induced tolerogenic phenotype in human DCs, which can help the better 
      understanding of processes involved in induction and resolution of chronic 
      inflammation and tolerance.
FAU - Salazar, Fabian
AU  - Salazar F
AD  - Division of Immunology, School of Life Sciences, Faculty of Medicine and Health 
      Sciences, University of Nottingham, United Kingdom.
FAU - Awuah, Dennis
AU  - Awuah D
AD  - Division of Immunology, School of Life Sciences, Faculty of Medicine and Health 
      Sciences, University of Nottingham, United Kingdom.
FAU - Negm, Ola H
AU  - Negm OH
AD  - Division of Immunology, School of Life Sciences, Faculty of Medicine and Health 
      Sciences, University of Nottingham, United Kingdom.
AD  - Medical Microbiology and Immunology Department, Mansoura University, Egypt.
FAU - Shakib, Farouk
AU  - Shakib F
AD  - Division of Immunology, School of Life Sciences, Faculty of Medicine and Health 
      Sciences, University of Nottingham, United Kingdom.
FAU - Ghaemmaghami, Amir M
AU  - Ghaemmaghami AM
AD  - Division of Immunology, School of Life Sciences, Faculty of Medicine and Health 
      Sciences, University of Nottingham, United Kingdom.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170303
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (AHR protein, human)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (CD274 protein, human)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (DC-specific ICAM-3 grabbing nonintegrin)
RN  - 0 (IDO1 protein, human)
RN  - 0 (IDO2 protein, human)
RN  - 0 (IL10 protein, human)
RN  - 0 (IL4 protein, human)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
RN  - 0 (Lectins, C-Type)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (PDCD1LG2 protein, human)
RN  - 0 (Programmed Cell Death 1 Ligand 2 Protein)
RN  - 0 (RELB protein, human)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (TLR4 protein, human)
RN  - 0 (TNF Receptor-Associated Factor 3)
RN  - 0 (TRAF3 protein, human)
RN  - 0 (Toll-Like Receptor 4)
RN  - 130068-27-8 (Interleukin-10)
RN  - 147337-75-5 (Transcription Factor RelB)
RN  - 207137-56-2 (Interleukin-4)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - B7-H1 Antigen/genetics/immunology
MH  - Basic Helix-Loop-Helix Transcription Factors/*genetics/immunology
MH  - Cell Adhesion Molecules/genetics/immunology
MH  - Cell Differentiation/drug effects
MH  - Dendritic Cells/cytology/drug effects/*immunology
MH  - Gene Expression Regulation
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology
MH  - Humans
MH  - Immune Tolerance
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/*genetics/immunology
MH  - Interleukin-10/genetics/immunology
MH  - Interleukin-4/pharmacology
MH  - Lectins, C-Type/genetics/immunology
MH  - Lipopolysaccharides/*pharmacology
MH  - Monocytes/cytology/drug effects/immunology
MH  - NF-kappa B/genetics/immunology
MH  - Primary Cell Culture
MH  - Programmed Cell Death 1 Ligand 2 Protein/genetics/immunology
MH  - Protein Serine-Threonine Kinases/genetics/immunology
MH  - Receptors, Aryl Hydrocarbon/*genetics/immunology
MH  - Receptors, Cell Surface/genetics/immunology
MH  - Signal Transduction
MH  - TNF Receptor-Associated Factor 3/genetics/immunology
MH  - Toll-Like Receptor 4/*genetics/immunology
MH  - Transcription Factor RelB/genetics/immunology
MH  - NF-kappaB-Inducing Kinase
PMC - PMC5335671
COIS- The authors declare no competing financial interests.
EDAT- 2017/03/04 06:00
MHDA- 2018/11/02 06:00
PMCR- 2017/03/03
CRDT- 2017/03/04 06:00
PHST- 2016/07/19 00:00 [received]
PHST- 2017/01/25 00:00 [accepted]
PHST- 2017/03/04 06:00 [entrez]
PHST- 2017/03/04 06:00 [pubmed]
PHST- 2018/11/02 06:00 [medline]
PHST- 2017/03/03 00:00 [pmc-release]
AID - srep43337 [pii]
AID - 10.1038/srep43337 [doi]
PST - epublish
SO  - Sci Rep. 2017 Mar 3;7:43337. doi: 10.1038/srep43337.