title: Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock.
abstract: Suppression of an excessive systemic inflammatory response is a promising and potent strategy for treating endotoxic sepsis. Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan catabolism, may play a critical role in various inflammatory disorders. In this study, we report a critical role for IDO in the dysregulated immune response associated with endotoxin shock. We found that IDO knockout (IDO(-/-)) mice and 1-methyl-D-tryptophan-treated, endotoxin-shocked mice had decreased levels of the cytokines, TNF-alpha, IL-6, and IL-12, and enhanced levels of IL-10. Blockade of IDO is thought to promote host survival in LPS-induced endotoxin shock, yet little is known about the molecular mechanisms that regulate IDO expression during endotoxin shock. In vitro and in vivo, IDO expression was increased by exogenous IL-12, but decreased by exogenous IL-10 in dendritic cells and splenic dendritic cells. Interestingly, whereas LPS-induced IL-12 levels in serum were higher than those of IL-10, the balance between serum IL-12 and IL-10 following challenge became reversed in IDO(-/-)- or 1-methyl-D-tryptophan-treated mice. Our findings demonstrate that the detrimental immune response to endotoxin shock may occur via IDO modulation. Restoring the IL-12 and IL-10 balance by blocking IDO represents a potential strategy for sepsis treatment.
authors.affiliation: Department of Microbiology and Immunology and National Research Laboratory of Dendritic Cell Differentiation and Regulation, Medical Research Institute, Pusan National University, College of Medicine, Busan, South Korea.
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.forename: Min-Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Chang
authors.forename: Jun Sik
authors.initials: JS
authors.lastname: Lee
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Jeong
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.forename: Won Sun
authors.initials: WS
authors.lastname: Park
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Su-Kil
authors.initials: SK
authors.lastname: Seo
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000235:genetics; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012772:Shock, Septic / Q000201:enzymology* / Q000276:immunology* / Q000517:prevention & control
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D008070:Lipopolysaccharides