Indoleamine 2,3-dioxygenase (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physio- pathologic conditions. We have recently demonstrated that IDO1 does not merely degrade tryptophan and produce immunoregulatory kynure- nines, but it also acts as a signal-transducing molecule, independently of its enzymic function. IDO1 signalling activity is triggered in plasmacytoid dendritic cells (pDCs) by transforming growth factor-b (TGF-b), an event that requires the non-canonical NF-jB pathway and induces long-lasting IDO1 expression and autocrine TGF-b production in a positive feedback loop, thus sustaining a stably regulatory phenotype in pDCs. IDO1 expression and catalytic function are defective in pDCs from non-obese diabetic (NOD) mice, a prototypic model of autoimmune diabetes. In the present study, we found that TGF-b failed to activate IDO1 signalling function as well as up-regulate IDO1 expression in NOD pDCs. Moreover, TGF-b-treated pDCs failed to exert immunosuppressive properties in vivo. Nevertheless, transfection of NOD pDCs with Ido1 prior to TGF-b treatment resulted in activation of the Ido1 promoter and induction of non-canonical NF-jB and TGF-b, as well as decreased pro- duction of the pro-inflammatory cytokines, interleukin 6 (IL-6) and tumour necrosis factor-a (TNF-a). Overexpression of IDO1 in TGF-b-treated NOD pDCs also resulted in pDC ability to suppress the in vivo presentation of a pancreatic b-cell auto-antigen. Thus, our data suggest that a correction of IDO1 expression may restore its dual function and thus represent a proper therapeutic manoeuvre in this autoimmune setting.
Forced IDO1 expression in dendritic cells restores immunoregulatory signalling in autoimmune diabetes
PALLOTTA, MARIA TERESA;ORABONA, Ciriana;BIANCHI, Roberta;VACCA, Carmine;FALLARINO, Francesca;BELLADONNA, Maria Laura;VOLPI, CLAUDIA;MONDANELLI, GIADA;GARGARO, MARCO;ALLEGRUCCI, Massimo;TALESA, Vincenzo Nicola;PUCCETTI, Paolo;GROHMANN, Ursula
2014
Abstract
Indoleamine 2,3-dioxygenase (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physio- pathologic conditions. We have recently demonstrated that IDO1 does not merely degrade tryptophan and produce immunoregulatory kynure- nines, but it also acts as a signal-transducing molecule, independently of its enzymic function. IDO1 signalling activity is triggered in plasmacytoid dendritic cells (pDCs) by transforming growth factor-b (TGF-b), an event that requires the non-canonical NF-jB pathway and induces long-lasting IDO1 expression and autocrine TGF-b production in a positive feedback loop, thus sustaining a stably regulatory phenotype in pDCs. IDO1 expression and catalytic function are defective in pDCs from non-obese diabetic (NOD) mice, a prototypic model of autoimmune diabetes. In the present study, we found that TGF-b failed to activate IDO1 signalling function as well as up-regulate IDO1 expression in NOD pDCs. Moreover, TGF-b-treated pDCs failed to exert immunosuppressive properties in vivo. Nevertheless, transfection of NOD pDCs with Ido1 prior to TGF-b treatment resulted in activation of the Ido1 promoter and induction of non-canonical NF-jB and TGF-b, as well as decreased pro- duction of the pro-inflammatory cytokines, interleukin 6 (IL-6) and tumour necrosis factor-a (TNF-a). Overexpression of IDO1 in TGF-b-treated NOD pDCs also resulted in pDC ability to suppress the in vivo presentation of a pancreatic b-cell auto-antigen. Thus, our data suggest that a correction of IDO1 expression may restore its dual function and thus represent a proper therapeutic manoeuvre in this autoimmune setting.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
