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Blockade of Indoleamine 2,3-Dioxygenase Protects Mice against Lipopolysaccharide-Induced Endotoxin Shock¹

In Duk Jung^*, Min-Goo Lee, Jeong Hyun Chang, Jun Sik Lee^*, Young-Il Jeong, Chang-Min Lee^*, Won Sun Park^¶, Jin Han^¶, Su-Kil Seo^||, Sang Yong Lee^# and Yeong-Min Park^2,*

^* 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; Department of Physiology, Korea University, College of Medicine, Seoul, South Korea; Department of Clinical Laboratory Science, Daegu Haany University, College of Health and Therapy, Gyeongsan, South Korea; Department of Microbiology, Pusan National University, College of Natural Science, Busan, South Korea; ^¶ National Research Laboratory for Mitochondria Signaling, FIRST Mitochondria Research Group, Department of Physiology and Biophysics, Inje University, College of Medicine, Busan, South Korea; ^|| Department of Microbiology, Inje University, College of Medicine, Busan, South Korea; and ^# Department of Internal Medicine, Busan Medical Center, Busan, South Korea

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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Korea Science and Engineering Foundation through the National Research Lab Program (R0A-2005-000-10008-0).

² Address correspondence and reprint requests to Dr. Yeong-Min Park, National Research Laboratory for Dendritic Cell Differentiation and Regulation, Department of Microbiology and Immunology, College of Medicine, Pusan National University, Busan, Korea. E-mail address: immunpym{at}pusan.ac.kr

³ Abbreviations used in this paper: DC, dendritic cell; 1-MT, 1-methyl-D-tryptophan; BMDC, bone marrow-derived DC; IDO, indoleamine 2,3-dioxygenase; MFI, mean fluorescence intensity; rm, recombinant mouse; WT, wild type.

⁴ The online version of this article contains supplementary material.