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

Abstract

Prostaglandin E2 (PGE 2 ), an abundantly produced lipid messenger in mammalian organisms, has been attributed to possess potent albeit ambivalent immunological functions. Recently, PGE 2 has been reported to stimulate the commonly believed immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway in human dendritic cells (DCs), but without promoting DC immunosuppressive activity. Here, we report that PGE 2 used as a DC maturation agent apparently has more diverse functions. PGE 2 -matured DCs acquired powerful IDO activity, which was sustained even after removing PGE 2 . These IDO-competent DCs were able to stimulate allogeneic T-cell proliferation, but achieved inhibitory activity as their content in DC/T-cell co-cultures increased. The DC inhibitory activity was reversed upon blockade of IDO activity, confirming that the suppressive effect was in fact mediated by IDO and occurred in a dose-dependent fashion. IDO-mediated T-cell suppression was restored upon re-stimulation of T cells in the absence of IDO activity, confirming its reversibility. T cells stimulated by PGE 2 -matured IDO-competent DCs were sensitized to produce multiple cytokines, comprising Th1, Th2, and Th17 phenotypes. Collectively, these data suggest that T cells stimulated by PGE 2 -matured DCs are not terminally differentiated and their ultimate type of response may be formed by microenvironmental conditions. Keywords: Human dendritic cells r IL-23 r Immunosuppression r Indoleamine 2,3-dioxygenase (IDO) r Prostaglandin E2 Supporting Information available online IntroductionThe intracellular enzyme indoleamine 2,3-dioxygenase (IDO) has a key function in tryptophan metabolism along the kynurenine pathway [1]. IDO's metabolic activity has been perceived to play a significant role in immune regulation. On the cellular level, the complementary effects of IDO-mediated metabolism, tryptophan starvation, and accumulation of immunomodulatory kynurenines Correspondence: Dr. Andreas Heitger e-mail: andreas.heitger@ccri.at at the antigen-presenting cell (APC)/T-cell synapse were proposed to effect regulation of T-cell activation and proliferation [1,2]. In fact, in the last decade, multiple studies corroborated the role of IDO in immune regulation and induction of tolerance (reviewed in [3,4]). IDO competence, i.e. IDO expression and activity [5,6], has been suggested to play a critical role in numerous clinical conditions entailing immune regulation, including tolerance induction in pregnancy [7], transplantation [8,9], and tumor immune evasion [10]. * These authors contributed equally to the work. Eur. J. Immunol. 2012Immunol. . 42: 1117Immunol. -1128 Effective induction of IDO competence is, by and large, restricted to cells of the monocyte/macrophage lineage and, in humans is predominantly found in dendritic cells (DCs) [4,11]. Numerous agents, most prominently interferon (IFN)-γ, have been described to induce IDO activity in DCs [12]. IDO induction is generally believed to represent a feedback mechanism of APC activation [8]. This understanding...

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“…2C). PGE 2 was reported to promote immune tolerance by regulating IDO expression (36,37). To corroborate whether COXderived PGE 2 acts as another potential humoral factor, we incubated MSC-treated PBMCs in the MLR with IDM, a nonselective COX inhibitor.…”

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“…Dead cells were removed after incubation at 37°C for 1.5 h, while living cells were differentiated with 1000 U/ml GM-CSF and 400 U/ml IL-4. Medium including cytokines was replaced on day 3 and iDCs were harvested on day 5 (Lanzinger et al, 2012). …”

“…Human PBMCs were separated from whole blood by density centrifugation (Lanzinger et al, 2012). PBMCs were cultured in RPMI-1640 medium supplemented with GlutaMAX–I (Gibco) and 2% human plasma (OP, Octapharma).…”

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“…In contrast to these findings, it was reported that the induction of IDO expression by PGE2 occurs through its receptor EP4 instead of EP2 and that PGE2-matured DCs were more capable of inducing both allogeneic and Ag-specific T cell proliferation when compared to DCs matured in the absence of this molecule (Krause et al 2007). More recently (Lanzinger et al 2012), it was shown that the stimulatory effect of PGE2-matured DCs on allogeneic T cells is variable and may be highly context dependent. When the IDO activity in the microenvironment is low, DCs act as effective stimulators of immune responses; however, once the enzymatic activity of IDO predominates, these cells suppress T cell responsiveness and/or promote regulatory T cell responses.…”

“…It has been shown that VEGF causes defective DC differentiation and maturation (Gabrilovich et al 1998, Menetrier-Caux et al 1998, Oyama et al 1998, Zhang et al 2003, Takahashi et al 2004). Moreover, the addition of VEGF to DC cultures promotes a weak stimulus for Ag-specific T cells due to an inhibitory effect mediated by VEGF receptor 1 (VEGFR1)/Flt-1 signalling (Nemeth et al 2004, Laxmanan et al 2005). Of the described receptors for VEGF, VEGFR1 is the primary mediator of DC maturation inhibition (Dikov et al 2005), whereas VEGFR2 is responsible for signal transduction in mature DCs, activating extracellular signal-regulated protein kinases 1 and 2 and impairing the DC stimulation of allogeneic lymphocytes (Kadambi et al 2001, Mimura et al 2007).…”