Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock.
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.
Jung
In Duk
ID
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.
Lee
Min-Goo
MG
Chang
Jeong Hyun
JH
Lee
Jun Sik
JS
Jeong
Young-Il
YI
Lee
Chang-Min
CM
Park
Won Sun
WS
Han
Jin
J
Seo
Su-Kil
SK
Lee
Sang Yong
SY
Park
Yeong-Min
YM
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
D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D008070:Lipopolysaccharides