Blockade of Indoleamine 2,3-Dioxygenase Protects Mice against Lipopolysaccharide-Induced Endotoxin Shock

• Published in: The Journal of immunology (1950) 2009-03, Vol.182 (5), p.3146-3154
• Main Authors: Jung, In Duk, Lee, Min-Goo, Chang, Jeong Hyun, Lee, Jun Sik, Jeong, Young-Il, Lee, Chang-Min, Park, Won Sun, Han, Jin, Seo, Su-Kil, Lee, Sang Yong, Park, Yeong-Min
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Cells - enzymology; Bone Marrow Cells - immunology; Cells, Cultured; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Dendritic Cells - enzymology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Models, Animal; Immunity, Innate - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase - deficiency; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - physiology; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Lipopolysaccharides - toxicity; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Shock, Septic - enzymology; Shock, Septic - immunology; Shock, Septic - prevention & control
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0803104

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.