Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy.
Glucocorticoid-induced tumor necrosis factor receptor (GITR) on T cells and its natural ligand, GITRL, on accessory cells contribute to the control of immune homeostasis. Here we show that reverse signaling through GITRL after engagement by soluble GITR initiates the immunoregulatory pathway of tryptophan catabolism in mouse plasmacytoid dendritic cells, by means of noncanonical NF-kappaB-dependent induction of indoleamine 2,3-dioxygenase (IDO). The synthetic glucocorticoid dexamethasone administered in vivo activated IDO through the symmetric induction of GITR in CD4(+) T cells and GITRL in plasmacytoid dendritic cells. The drug exerted IDO-dependent protection in a model of allergic airway inflammation. Modulation of tryptophan catabolism via the GITR-GITRL coreceptor system might represent an effective therapeutic target in immune regulation. Induction of IDO could be an important mechanism underlying the anti-inflammatory action of corticosteroids.
Grohmann
Ursula
U
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06126 Perugia, Italy.
Volpi
Claudia
C
Fallarino
Francesca
F
Bozza
Silvia
S
Bianchi
Roberta
R
Vacca
Carmine
C
Orabona
Ciriana
C
Belladonna
Maria L
ML
Ayroldi
Emira
E
Nocentini
Giuseppe
G
Boon
Louis
L
Bistoni
Francesco
F
Fioretti
Maria C
MC
Romani
Luigina
L
Riccardi
Carlo
C
Puccetti
Paolo
P
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D006967:Hypersensitivity / Q000503:physiopathology* / Q000517:prevention & control*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D051379:Mice; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000502:physiology
D053450:Glucocorticoid-Induced TNFR-Related Protein; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; C478967:TNFSF18 protein, human; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; D003907:Dexamethasone