PMID- 29295842
OWN - NLM
STAT- MEDLINE
DCOM- 20190514
LR  - 20210202
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 131
IP  - 13
DP  - 2018 Mar 29
TI  - Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation 
      syndrome in mice.
PG  - 1430-1441
LID - 10.1182/blood-2017-06-789552 [doi]
AB  - The term macrophage activation syndrome (MAS) defines a severe, potentially fatal 
      disorder characterized by overwhelming inflammation and multiorgan involvement. 
      Interleukin-18 (IL-18) is a proinflammatory cytokine belonging to the IL-1 
      family, the activity of which is regulated by its endogenous inhibitor IL-18 
      binding protein (IL-18BP). Elevated IL-18 levels have been reported in patients 
      with MAS. Herein, we show that on repeated toll-like receptor 9 (TLR9) 
      stimulation with unmethylated cytosine guanine dinucleotide containing 
      single-stranded DNA (CpG), IL-18BP(-/-) mice display severe MAS manifestations, 
      including increased weight loss, splenomegaly, anemia, thrombocytopenia, 
      hyperferritinemia, and bone marrow hemophagocytosis as compared with wild-type 
      mice. Serum-free IL-18 was detected in CpG-treated IL-18BP(-/-) mice only. Levels 
      of interferon-gamma (IFN-gamma) and of IFN-gamma signature genes, such as the chemokine Cxcl9 
      or the transcription factor CIIta, were significantly increased in IL-18BP(-/-) 
      mice. Blocking IL-18 receptor signaling attenuated the severity of MAS and IFN-gamma 
      responses in IL-18BP(-/-) mice. Blocking IFN-gamma had comparable effects to IL-18 
      inhibition on most MAS manifestations. Our data indicate that endogenous IL-18BP 
      exerts a protective role in CpG-induced MAS and that IL-18, which acts upstream 
      of IFN-gamma, is involved in the severity of MAS.
CI  - (c) 2018 by The American Society of Hematology.
FAU - Girard-Guyonvarc'h, Charlotte
AU  - Girard-Guyonvarc'h C
AD  - Division of Rheumatology, Department of Internal Medicine Specialties, University 
      Hospital, Geneva, Switzerland; and Department of Pathology-Immunology, University 
      of Geneva School of Medicine, Geneva, Switzerland.
FAU - Palomo, Jennifer
AU  - Palomo J
AD  - Division of Rheumatology, Department of Internal Medicine Specialties, University 
      Hospital, Geneva, Switzerland; and Department of Pathology-Immunology, University 
      of Geneva School of Medicine, Geneva, Switzerland.
FAU - Martin, Praxedis
AU  - Martin P
AD  - Division of Rheumatology, Department of Internal Medicine Specialties, University 
      Hospital, Geneva, Switzerland; and Department of Pathology-Immunology, University 
      of Geneva School of Medicine, Geneva, Switzerland.
FAU - Rodriguez, Emiliana
AU  - Rodriguez E
AD  - Division of Rheumatology, Department of Internal Medicine Specialties, University 
      Hospital, Geneva, Switzerland; and Department of Pathology-Immunology, University 
      of Geneva School of Medicine, Geneva, Switzerland.
FAU - Troccaz, Sabina
AU  - Troccaz S
AD  - Division of Rheumatology, Department of Internal Medicine Specialties, University 
      Hospital, Geneva, Switzerland; and Department of Pathology-Immunology, University 
      of Geneva School of Medicine, Geneva, Switzerland.
FAU - Palmer, Gaby
AU  - Palmer G
AD  - Division of Rheumatology, Department of Internal Medicine Specialties, University 
      Hospital, Geneva, Switzerland; and Department of Pathology-Immunology, University 
      of Geneva School of Medicine, Geneva, Switzerland.
FAU - Gabay, Cem
AU  - Gabay C
AUID- ORCID: 0000-0001-6853-3063
AD  - Division of Rheumatology, Department of Internal Medicine Specialties, University 
      Hospital, Geneva, Switzerland; and Department of Pathology-Immunology, University 
      of Geneva School of Medicine, Geneva, Switzerland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180102
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (CPG-oligonucleotide)
RN  - 0 (Chemokine CXCL9)
RN  - 0 (Cxcl9 protein, mouse)
RN  - 0 (IFNG protein, mouse)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Interleukin-18)
RN  - 0 (MHC class II transactivator protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Oligodeoxyribonucleotides)
RN  - 0 (Tlr9 protein, mouse)
RN  - 0 (Toll-Like Receptor 9)
RN  - 0 (Trans-Activators)
RN  - 0 (interleukin-18 binding protein)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
CIN - Blood. 2018 Mar 29;131(13):1393-1394. PMID: 29599143
MH  - Animals
MH  - Chemokine CXCL9/genetics/immunology
MH  - Intercellular Signaling Peptides and Proteins/genetics/immunology
MH  - Interferon-gamma/genetics/immunology
MH  - Interleukin-18/genetics/*immunology
MH  - Macrophage Activation Syndrome/chemically induced/genetics/*immunology/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Nuclear Proteins/genetics/immunology
MH  - Oligodeoxyribonucleotides/adverse effects/pharmacology
MH  - Signal Transduction/drug effects/genetics/*immunology
MH  - Toll-Like Receptor 9/agonists/genetics/*immunology
MH  - Trans-Activators/genetics/immunology
EDAT- 2018/01/04 06:00
MHDA- 2019/05/15 06:00
CRDT- 2018/01/04 06:00
PHST- 2017/06/12 00:00 [received]
PHST- 2017/12/20 00:00 [accepted]
PHST- 2018/01/04 06:00 [pubmed]
PHST- 2019/05/15 06:00 [medline]
PHST- 2018/01/04 06:00 [entrez]
AID - S0006-4971(20)32360-0 [pii]
AID - 10.1182/blood-2017-06-789552 [doi]
PST - ppublish
SO  - Blood. 2018 Mar 29;131(13):1430-1441. doi: 10.1182/blood-2017-06-789552. Epub 
      2018 Jan 2.