Curcumin Suppresses the Induction of Indoleamine 2,3-Dioxygenase by Blocking the Janus-activated Kinase-Protein Kinase Cδ-STAT1 Signaling Pathway in Interferon-γ-stimulated Murine Dendritic Cells

Abstract

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-␥ (IFN␥)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme inT-cell suppression-mediated immune tolerance to tumors. STAT1 phosphorylation appears to play an important role in the control of IDO expression by IFN␥, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFN␥-induced IDO expression in bone marrow-derived dendritic cells. In addition, we demonstrate that curcumin, an active component of turmeric, significantly inhibited the induction of IDO expression and activity by IFN␥. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase C␦ phosphorylation in bone marrow-derived DCs, suppressing the subsequent translocation and binding of STAT1 to the GAS element of the IRF-1 promoter. Coincident with these inhibitory effects on IFN␥-induced IDO expression, curcumin reversed IDO-mediated suppression of T-cell responses. Our results, thus, suggest that down-regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers.Dendritic cells (DCs) 3 are professional antigen-presenting cells that function as immune sentinels for the initiation of T-cell responses against microbial pathogens and tumors (1, 2). It is now well known that DCs not only induce immunity but are also important for the induction of T-cell tolerance. In particular, murine CD11c ϩ DCs that coexpress the markers CD8␣, B220, DX5, and DEC205 promote tolerance rather than immunity to specific antigens (3, 4). One of the mechanisms that might contribute to this tolerance in antigen-presenting cells involves the expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO).IDO catalyzes the initial and rate-limiting step in the catabolism of tryptophan along the kynurenine pathway. IDO has also recently been established as a key enzyme in T-cell suppression and the induction of immune tolerance (5-7). The expression of IDO by various cell types has broad immunological significance. In particular, in many tumors and tolerant antigen-presenting cells, IDO degrades tryptophan to kynurenine, leading to the depletion of tryptophan and resulting in the suppression of T-cell proliferation (8 -10). Recent in vivo studies suggest that IDO-expressing DCs isolated from tumordraining lymph nodes contribute to the progression of tumors by creating local immunosuppression (11-13).The control of IDO transcription is complex and cell typespecific (6). A number of pathways, including the mitogen-activated protein kinase and noncanonical NF-B signaling pathways as well as the Janus-activated kinase-signal transducer and activator of transcription (JAK-STAT) pathway, can modulate IDO expression in response to a variety of stimuli (14,15). In macrophages and DCs, transcription of the IDO gene is s...

Immunotherapy with Costimulatory Dendritic Cells To Control Autoimmune Inflammation

“…As shown in this article, DC IDO expression and induction by LPS/IFN-g may also occur in a RelBindependent fashion. In support of a signaling pathway independent of the alternate NF-kB pathway, IDO is induced through STAT1 and IRF1 signaling downstream of the IFN-g receptor in DCs (60,61 Our conclusions that IFN-g and IDO are critical components of effective therapeutic immunoregulation of autoimmune disease are strongly supported by the literature in strains of mice prone to spontaneous Th1/Th17-mediated autoimmune disease. Although T EM and Treg IFN-g was induced in the current studies, regulatory IFN-g could also derive from NK or NKT cells to similar regulatory effect.…”

MicroRNA‐181a Regulates Local Immune Balance by Inhibiting Proliferation and Immunosuppressive Properties of Mesenchymal Stem Cells

“…IL-6 are not direct targets of miR181a and previous studies reported that IL-6 expression are regulated by MAPK, NF-jB, and STAT1 pathways [35][36][37][38][39]. Based on this knowledge, we used MAPK, NF-jB, and STAT1 pathway inhibitors to determine whether upregulation of IL-6 via miR-181a was dependent on these pathways.…”

Immunomodulation of Curcumin on Adoptive Therapy with T Cell Functional Imaging in Mice

“…Although the exact mechanism to suppress T cells used by DCs remains poorly understood, some work has shown that murine and human IDO-expressing DCs in TDLNs are able to degrade tryptophan and create profound T-cell anergy (41,42). Interestingly, curcumin also inhibits IDO significantly in IFN-g-stimulated murine bone marrow-derived DCs in vitro, resulting in reversing IDO-mediated suppression of T-cell function (43). Therefore, the effect of curcumin on IDO-expressing DCs of the host may be another mechanism contributing to enhanced efficacy of adoptive therapy and is worthy of further study.…”