Inhibition of experimental asthma by indoleamine 2,3-dioxygenase

Tomoko Hayashi

Lucinda Beck

Cyprian Rossetto

Xing Gong

^{University of California, San Diego, Department of Medicine, La Jolla, California, USA.}^{Central Research Institute, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.}

Address correspondence to: Eyal Raz, University of California, San Diego, Department of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0663, USA. Phone: (858) 534-5444; Fax: (858) 534-5399; E-mail: ude.dscu@zare.

Received 2004 Feb 9; Accepted 2004 May 18.

Abstract

Epidemiological evidence points to the inverse relationship between microbial exposure and the prevalence of allergic asthma and autoimmune diseases in Westernized countries. The molecular basis for this observation has not yet been completely delineated. Here we report that the administration of certain toll-like receptor (TLR) ligands, via the activation of innate immunity, induces high levels of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan catabolism in various organs. TLR9 ligand–induced pulmonary IDO activity inhibits Th2-driven experimental asthma. IDO activity expressed by resident lung cells rather than by pulmonary DCs suppressed lung inflammation and airway hyperreactivity. Our results provide a mechanistic insight into the various formulations of the hygiene hypothesis and underscore the notion that activation of innate immunity can inhibit adaptive Th cell responses.

Abstract

Acknowledgments

We thank Nissi Varki (University of California, San Diego) for histological evaluation and Robert Coffman (Dynavax Technologies Corp.) for helpful comments. This work was supported by NIH grants AI40682, DK35108, AR47360 (to E. Raz), and AI56453 (to D. Carson). E. Raz is supported by a grant from Dynavax Technologies Corp.

Acknowledgments

Footnotes

Nonstandard abbreviations used: airway hyperreactivity (AHR); 7-amino actinomycin D (7-AAD); bone marrow–derived DC (BMDC); enhanced pause (Penh); flagellin (Flag); IFN-α/β receptor (IFN-α/βR); IL-1β receptor (IL-1βR); immunostimulatory sequence oligodeoxynucleotide (ISS-ODN); indoleamine 2,3 dioxygenase (IDO); kynurenine (KYN); methacholine (MCh); 1-methyl-dl-tryptophan (M-trp); Pam3Cys-Ser-(Lys)-4-3HCl (P3C); poly I:C (pI:C); regulatory T cell (Treg); transgenic (Tg); tryptophan (trp).

Conflict of interest: The authors have declared that no conflict of interest exists.

Footnotes

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