title: Platelet-activating Factor Mediates Endotoxin Tolerance by Regulating Indoleamine 2,3-Dioxygenase-dependent Expression of the Suppressor of Cytokine Signaling 3.
abstract: Indoleamine 2,3-dioxygenase (IDO) mediates immune tolerance, and suppressor of cytokine signaling 3 (SOCS3) negatively regulates the JAK/STAT signal transduction pathway. We determined previously that platelet-activating factor (PAF) protects mice against LPS-induced endotoxic shock, but its detailed mechanism of action was unknown. We performed survival experiments inIDO+/+andIDO-/-mice using an LPS-induced endotoxemia model and rated organ injury (neutrophil infiltration and liver function). Using ELISA and Western blotting, we also investigated the mechanism of PAF-mediated endotoxin tolerance during endotoxemia. PAF-mediated endotoxin tolerance was dependent on IDOin vivoandin vitroand was not observed inIDO-/-mice. JAK/STAT signaling, crucial for SOCS3 expression, was also impaired in the absence of IDO. In an IDO- and STAT-dependent manner, PAF mediated a decrease in IL-12 and a dramatic increase in IL-10 and reduced mouse mortality. In addition, PAF attenuated LPS-mediated neutrophil infiltration into the lungs and interactions between neutrophil-like (THP-1) and endothelial cells (human umbilical vein endothelial cells). These results indicate that PAF-mediated endotoxin tolerance is initiated via IDO- and JAK/STAT-dependent expression of SOCS3. Our study has revealed a novel tolerogenic mechanism of IDO action and an important association between IDO and SOCS3 with respect to endotoxin tolerance.
authors.affiliation: Department of Infectious Diseases, Armed Forces Medical Research Institute, 90bun, Jaunro, Yuseong-gu, Daejeon 305-878, South Korea.
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Noh
authors.affiliation: Department of Immunology, College of Medicine, Konkuk University, Seoul 143-701, South Korea.
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.affiliation: Department of Immunology, College of Medicine, Konkuk University, Seoul 143-701, South Korea.
authors.forename: Gil Sun
authors.initials: GS
authors.lastname: Cha
authors.affiliation: Department of Microbiology, Chonbuk National University Medical School, Jeonju 561-182, South Korea. Electronic address: iamtom@chonbuk.ac.kr.
authors.forename: Myung-Kwan
authors.initials: MK
authors.lastname: Han
authors.affiliation: Department of Immunology, College of Medicine, Konkuk University, Seoul 143-701, South Korea. Electronic address: immun3023@kku.ac.kr.
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology*; D019446:Endotoxemia / Q000276:immunology* / Q000473:pathology; D017353:Gene Deletion; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010972:Platelet Activating Factor / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000276:immunology*
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein
keywords: dendritic cell; endotoxin; glycogen synthase kinase 3 (GSK-3); immunosuppressor; indoleamine-pyrrole 2,3-dioxygenase (IDO1)