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

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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

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ASJC Scopus subject areas

  • Immunology

Cite this

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