Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock

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, Yeong Min Park

Research output: Contribution to journalArticle

75 Citations (Scopus)

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-α, 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.

Original languageEnglish
Pages (from-to)3146-3154
Number of pages9
JournalJournal of Immunology
Volume182
Issue number5
DOIs
Publication statusPublished - 2009 Mar 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Jung, I. D., Lee, M. G., Chang, J. H., Lee, J. S., Jeong, Y. I., Lee, C. M., Park, W. S., Han, J., Seo, S. K., Lee, S. Y., & Park, Y. M. (2009). Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock. Journal of Immunology, 182(5), 3146-3154. https://doi.org/10.4049/jimmunol.0803104