A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation

Abstract

Prostaglandins, a family of lipidic molecules released during inflammation, display immunomodulatory properties in several models. One use includes exposure of monocyte-derived dendritic cells (DCs) to a cocktail of cytokines that contains prostaglandin E 2 (PGE 2 ) for purposes of maturation; such cells are currently being used for cancer immunotherapy trials. Our analysis of the transcription profile of DCs matured in the presence of tumor necrosis factor ␣ (TNF␣) and PGE 2 revealed a strong up-regulation of indoleamine 2-3 dioxygenase (IDO), an enzyme involved in tryptophan catabolism and implicated in both maternal and T-cell tolerance. Using quantitative assays to monitor levels of IDO mRNA, protein expression, and enzyme activity, we report that PGE 2 induces mRNA expression of IDO; however, a second signal through TNF receptor (TNF- R IntroductionProstaglandin E 2 (PGE 2 ) is a catabolite of arachidonic acid and is generated by the sequential activity of cyclo-oxygenase (COX) and prostaglandin E synthase. 1 Produced during inflammation, PGE 2 is believed to act as a counter-inflammatory agent, modulating inflammatory responses and helping to restore tissue homeostasis. For example, PGE 2 has been reported to suppress T-cell proliferation, 2,3 inhibit macrophage and dendritic-cell cytokine production (eg, and tumor necrosis factor ␣ [TNF␣] 4,5 ), and modulate antigen presentation by down-regulating expression of major histocompatability complex (MHC) II. 6 Additionally, PGE 2 may skew CD4 ϩ T cells toward a T helper cell type 2 (T H 2) phenotype 7,8 and B cells toward immunoglobulin E (IgE) production. 5 In other studies, PGE 2 has been shown to play a role in T-cell development 9 and may be an inhibitor of apoptosis in doublepositive thymocytes. 10 Consistent with these reports, expression of various prostaglandin biosynthetic enzymes and receptors has been detected in the thymus. 11 Dendritic cells (DCs) are considered to be the only antigenpresenting cell (APC) capable of priming naive T cells, and they are also potent stimulators of recall responses. 12 Briefly, DCs exist in the periphery as immature cells where they serve as "sentinels," responsible for capturing antigen. Upon maturation, DCs migrate to the draining lymphoid organs, where they may initiate immune responses. This ability to traffic out of peripheral tissue with captured antigen and enter the afferent lymph is unique to the DCs, making them the appropriate carrier of tissue-restricted antigen to lymphoid organs for the initiation of immunity. 12 Their role in priming T cells has also prompted much interest in discovering strategies to efficiently use DCs carrying tumor antigen for adoptive transfer and immunization of tumor-reactive T cells. Our understanding of DC biology, however, has not resulted in overwhelming success; few DC-based studies have reported an effect greater than the 10% rate achieved by Coley. [13][14][15] Given that DCs are capable of mediating both T-cell priming as well as T-cell inactivation (tolerance), a deeper ...

On watching the watchers: IDO and type I/II IFN

“…2007. 37: 876-879 mechanism of IDO induction by a tolerogenic ligand, autocrine IFN-a will have an obligatory role in IDO induction (perhaps due to a required STAT1 function), and IFN-c from whatever source may or may not contribute to a sustained effect on IDO depending on environmental factors; in general DC terms, however, regulation of functional IDO is complex, is cell-type specific [2], and it involves interference with cytokine signaling [16] and transcription factor activity [17], modulation of continuous inhibitory effects on IDO function [13,18], and post-translational modifications of IDO itself [19].…”

Pulmonary stromal cells induce the generation of regulatory DC attenuating T‐cell‐mediated lung inflammation

“…Since lung fibroblasts secreted PGE2 [15,16], and PGE2 could drive human imDC to differentiate into regulatory cells in vitro [17][18][19], we examined the PGE2 secretion of murine pulmonary stromal cells (MPSC) and confirmed that MPSC secreted PGE2 (data not shown). Therefore, we explored the role of MPSC-derived PGE2 in the differentiation of imDC into DCreg.…”

“…Moreover, we used 50% supernatant (SN) from MPSC to incubate imDC and found that the resulting DCreg had inhibitory ability, although their ability to inhibit T-cell proliferation was weaker than that of DCreg derived from co-culture with MPSC ( Fig. 3), further confirming that soluble factors are involved in the differentiation of DCreg.Since lung fibroblasts secreted PGE2 [15,16], and PGE2 could drive human imDC to differentiate into regulatory cells in vitro [17][18][19], we examined the PGE2 secretion of murine pulmonary stromal cells (MPSC) and confirmed that MPSC secreted PGE2 (data not shown). Therefore, we explored the role of MPSC-derived PGE2 in the differentiation of imDC into DCreg.…”

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

“…Our data, in composite, support the view of a diverse and ambivalent effect of PGE 2 -matured DCs on stimulated T cells. PGE 2 , included into the cytokine cocktail used for maturation of human DCs, has, in addition to its known effect on enhancing DC migration, recently been demonstrated to be followed by the induction of IDO competence [17,18]. The underlying mechanism, that is which of the two prostaglandin receptors active in human DCs, EP2, or EP4, is involved in IDO induction, has so far yielded opposing results [17,21], and deserves further extensive and systematic studies for clarification.…”

“…IDO induction is generally believed to represent a feedback mechanism of APC activation [8]. This understanding is supported by the observation that neopterin, a guanosine triphosphate (GTP) cleavage product [13], has been found to be closely linked to IDO activity in a wide spectrum of conditions involving immune activation [14][15][16].In some recent reports, also prostaglandin E2 (PGE 2 ) was described to up-regulate IDO competence in human DCs [17,18]. Induction of IDO competence through PGE 2 occurred, like in human DC maturation [19,20], in concert with TNF-α.…”