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-γ (IFNγ)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme in T-cell suppression-mediated immune tolerance to tumors. STAT1 phosphorylation appears to play an important role in the control of IDO expression by IFNγ, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFNγ-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 IFNγ. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase Cδ 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 IFNγ-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. Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-γ (IFNγ)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme in T-cell suppression-mediated immune tolerance to tumors. STAT1 phosphorylation appears to play an important role in the control of IDO expression by IFNγ, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFNγ-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 IFNγ. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase Cδ 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 IFNγ-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) 3The abbreviations used are: DC, dendritic cell; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; PBS, phosphate-buffered saline; OVA, ovalbumin; ChIP, chromatin Immunoprecipitation; LPS, lipopolysaccharide; JAK, Janus-activated kinase; STAT, signal transducer and activator of transcription; BMDC, bone marrow (BM)-derived DC; IRF-1, IFN-regulatory factor-1; PKC, protein kinase C; Ab, antibodies; RT, reverse transcriptase; CFSE, carboxyfluorescein diacetate succinimidyl ester; GAS, gamma interferon activation sequences. are professional antigen-presenting cells that function as immune sentinels for the initiation of T-cell responses against microbial pathogens and tumors (1Granucci F. Zanoni I. Feau S. Ricciardi-Castagnoli P. EMBO J.. 2003; 22: 2546-2551Google Scholar, 2Steinman R.M. Annu. Rev. Immunol.. 1991; 9: 271-296Google Scholar). 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+ DCs that coexpress the markers CD8α, B220, DX5, and DEC205 promote tolerance rather than immunity to specific antigens (3Belz G.T. Behrens G.M. Smith C.M. Miller J.F. Jones C. Lejon K. Fathman C.G. Mueller S.N. Shortman K. Carbone F.R. Heath W.R. J. Exp. Med.. 2002; 196: 1099-1104Google Scholar, 4Wakkach A. Fournier N. Brun V. Breittmayer J.P. Cottrez F. Groux H. Immunity.. 2003; 18: 605-617Google Scholar). 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 (5Mellor A.L. Munn D.H. Immunol. Today.. 1999; 20: 469-473Google Scholar, 6Mellor A.L. Munn D.H. Nat. Rev. Immunol.. 2004; 4: 762-774Google Scholar, 7Munn D.H. Mellor A.L. J. Clin. Investig.. 2007; 117: 1147-1154Google Scholar). 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 (8Burke F. Knowles R.G. East N. Balkwill F.R. Int. J. Cancer.. 1995; 60: 115-122Google Scholar, 9Hwu P. Du M.X. Lapointe R. Do M. Taylor M.W. Young H.A. J. Immunol.. 2000; 164: 3596-3599Google Scholar, 10Munn D.H. Shafizadeh E. Attwood J.T. Bondarev I. Pashine A. Mellor A.L. J. Exp. Med.. 1999; 189: 1363-1372Google Scholar). Recent in vivo studies suggest that IDO-expressing DCs isolated from tumor-draining lymph nodes contribute to the progression of tumors by creating local immunosuppression (11Fallarino F. Grohmann U. Vacca C. Bianchi R. Orabona C. Spreca A. Fioretti M.C. Puccetti P. Cell Death Differ.. 2002; 9: 1069-1077Google Scholar, 12Mellor A.L. Chandler P. Baban B. Hansen A.M. Marshall B. Pihkala J. Waldmann H. Cobbold S. Adams E. Munn D.H. Int. Immunol.. 2004; 16: 1391-1401Google Scholar, 13Munn D.H. Sharma M.D. Hou D. Baban B. Lee J.R. Antonia S.J. Messina J.L. Chandler P. Koni P.A. Mellor A.L. J. Clin. Investig.. 2004; 114: 280-290Google Scholar). The control of IDO transcription is complex and cell type-specific (6Mellor A.L. Munn D.H. Nat. Rev. Immunol.. 2004; 4: 762-774Google Scholar). A number of pathways, including the mitogen-activated protein kinase and noncanonical NF-κB 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 (14Jung I.D. Lee C.M. Jeong Y.I. Lee J.S. Park W.S. Han J. Park Y.M. FEBS Lett.. 2007; 581: 1449-1456Google Scholar, 15Tas S.W. Vervoordeldonk M.J. Hajji N. Schuitemaker J.H. van der Sluijs K.F. May M.J. Ghosh S. Kapsenberg M.L. Tak P.P. de Jong E.C. Blood.. 2007; 110: 1540-1549Google Scholar). In macrophages and DCs, transcription of the IDO gene is strongly induced by IFNγ (6Mellor A.L. Munn D.H. Nat. Rev. Immunol.. 2004; 4: 762-774Google Scholar). In bone marrow-derived DCs (BMDCs), the precise regulatory mechanisms underlying IFNγ-induced IDO expression remain unclear. IFNγ-induced gene expression has been closely linked to the JAK-STAT signaling pathway (16Chon S.Y. Hassanain H.H. Gupta S.L. J. Biol. Chem.. 1996; 271: 17247-17252Google Scholar, 17Platanias L.C. Nat. Rev. Immunol.. 2005; 5: 375-386Google Scholar). After IFNγ binds to its surface receptor, the receptor-associated JAK1 and JAK2 become activated and regulate the downstream phosphorylation of STAT1 on the tyrosine 701. Tyrosine phosphorylation of STAT results in the formation of STAT1-STAT1 homodimers, which translocate into the nucleus and bind to the distinct IFNγ-activated site (GAS) element in the promoters of IFNγ-activated genes, including IFN-regulatory factor-1 (IRF-1), to initiate gene transcription (17Platanias L.C. Nat. Rev. Immunol.. 2005; 5: 375-386Google Scholar). In addition, STAT1 is also phosphorylated at serine 727 by protein kinase C δ (PKCδ), a phosphorylation event that is required for maximal induction of gene transcription (18Wen Z. Zhong Z. Darnell Jr., J.E. Cell.. 1995; 82: 241-250Google Scholar). Both tyrosine and serine phosphorylation of STAT1 after the activation of JAKs and PKCδ are critically important in the transcription of IFNγ-associated genes (17Platanias L.C. Nat. Rev. Immunol.. 2005; 5: 375-386Google Scholar). IFNγ-induced gene transcription in various cell types is also regulated by IRF-1, which transactivates multiple effector genes (20Ma X. Chow J.M. Gri G. Carra G. Gerosa F. Wolf S.F. Dzialo R. Trinchieri G. J. Exp. Med.. 1996; 183: 147-157Google Scholar, 21Martin E. Nathan C. Xie Q.W. J. Exp. Med.. 1994; 180: 977-984Google Scholar). These regulatory effects are mediated by cooperative binding of STAT1 and IRF-1 to their cognate promoter sequence and are essential for IFNγ-induced gene transcription (19Decker T. Kovarik P. Oncogene.. 2000; 19: 2628-2637Google Scholar). Curcumin (1,7-bis(4-hydrosy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a phenolic natural product isolated from the rhizome of Curcuma longa, is the active component of turmeric. It exhibits anti-oxidant, anti-inflammatory, and anti-carcinogenic activities (22Aggarwal B.B. Shishodia S. Takada Y. Banerjee S. Newman R.A. Bueso-Ramos C.E. Price J.E. Clin. Cancer Res.. 2005; 11: 7490-7498Google Scholar, 23Ireson C. Orr S. Jones D.J. Verschoyle R. Lim C.K. Luo J.L. Howells L. Plummer S. Jukes R. Williams M. Steward W.P. Gescher A. Cancer Res.. 2001; 61: 1058-1064Google Scholar, 24Kawamori T. Lubet R. Steele V.E. Kelloff G.J. Kaskey R.B. Rao C.V. Reddy B.S. Cancer Res.. 1999; 59: 597-601Google Scholar, 25Ruby A.J. Kuttan G. Babu K.D. Rajasekharan K.N. Kuttan R. Cancer Lett.. 1995; 94: 79-83Google Scholar), implying that curcumin engages the immune system on multiple levels. On the basis of these multiple biological activities, curcumin has been suggested to have therapeutic potential in the treatment or prevention of several inflammatory diseases and cancer (26Johnson J.J. Mukhtar H. Cancer Lett.. 2007; 255: 170-181Google Scholar, 27Stan S.D. Kar S. Stoner G.D. Singh S.V. J. Cell. Biochem.. 2008; 104: 339-356Google Scholar). The rationale for the present study stems from previous observations that several antioxidants inhibit IDO in INF-γ-activated macrophages through posttranslational or transcriptional regulation of IDO expression (28Thomas S.R. Salahifar H. Mashima R. Hunt N.H. Richardson D.R. Stocker R. J. Immunol.. 2001; 166: 6332-6340Google Scholar). In addition, we have previously reported that several antioxidants inhibit IDO expression in IFNγ-induced BMDCs (29Jeong Y.I. Jung I.D. Lee J.S. Lee C.M. Lee J.D. Park Y.M. Biochem. Biophys. Res. Commun.. 2007; 354: 1004-1009Google Scholar, 30Kim S.I. Jeong Y.I. Jung I.D. Lee J.S. Lee C.M. Yoon M.S. Seong E.Y. Kim J.I. Lee J.D. Park Y.M. Int. Immunopharmacol.. 2007; 7: 805-815Google Scholar, 31Lee H.J. Jeong Y.I. Lee T.H. Jung I.D. Lee J.S. Lee C.M. Kim J.I. Joo H. Lee J.D. Park Y.M. Biochem. Pharmacol.. 2007; 73: 1412-1421Google Scholar). The present study was, thus, designed to investigate whether curcumin, acting as an antioxidant, could inhibit IDO expression and activity in IFNγ-induced murine BMDCs and, if so, to elucidate the underlying regulatory mechanism. In this report we demonstrate a novel biological activity of curcumin in IDO-mediated immune tolerance, showing that curcumin significantly inhibited the expression and enzymatic functions of IDO in IFNγ-stimulated murine BMDCs, thereby reversing IDO-mediated T-cell suppression. We further demonstrate that curcumin regulates IFNγ-induced IDO expression by targeting JAK1 and PKCδ signaling pathways. Mice—Male 8–10-week-old C57BL/6 (H-2Kb and I-Ab) mice were purchased from the Korean Institute of Chemistry Technology (Daejeon, Korea). OT-1 T-cell receptor transgenic mice in the C57BL/6 background were purchased form The Jackson Laboratory (Bar Harbor, ME). They were bred using and for transgenic of from the with and and using with of their for were The were in a specific and used in with the for and and were purchased from Curcumin with a of and purchased from and were purchased from or used to the expression of and were purchased from protein by and were purchased from Cell and IDO purchased from against and PKCδ were purchased from of were from murine cells as by K. M. N. H. M. S. S. R.M. J. Exp. Med.. with from the and of C57BL/6 and of cells with The cells were in in with and at On of the cells were and On of the cells and DCs were for or On or of the cells for subsequent the DCs were with and to through to the The of the cell IDO by from cells isolated using the the used for the of the of The used for of IDO and were for for for for for were on a we the cell of to on a and to a After the with and with or the with the using an system for IDO the and the has been reported by and D. M.L. Blood.. 2005; we used the for IDO cells were by the by and an of IDO PBS, and were purchased from After at the with the of of and further for at After the with an of in The to for and the at in a of were used as A kynurenine by the at of kynurenine at of One of IDO activity as the of enzyme of The of protein in the to the using the protein with as were from using a T-cell to be by after with The were in and and by carboxyfluorescein diacetate succinimidyl as previously A. M. A. F. Nat. Immunol.. 2000; Scholar). In OT-1 were in in After of at cells were in and in with DCs cells from of C57BL/6 were with or curcumin were for in the or of IFNγ DCs were or with by S. Y. at for and OT-1 were in in with DCs After of the cells were and with to on the OT-1 and by were using a to a of the cells were with for at to the were and with and the of the protein used to the and were to and on for Cell were to the to and and at for at The cell were in and and with a of protein for at with The after the by and with of a against STAT1 at The were by protein for at with were with and by in were with of reverse to to a of the to for were with for at and with a were by The of IRF-1 promoter are as IRF-1 IRF-1 reverse were at with are as the of used to to control multiple were using multiple a than Curcumin the and of IDO in IFNγ-stimulated investigate the of curcumin on IFNγ-induced IDO expression, we BMDCs with or curcumin and cells with IFNγ. we that IFNγ induced a in the transcription of the IDO gene in BMDCs, an that inhibited in a by curcumin that curcumin also inhibited IFNγ-induced IDO expression at the protein We have previously that curcumin has on cell at curcumin Kim Lee Yoon M.S. Lee H.J. Lee C.M. Park Park Y.M. J. Immunol.. 2005; Scholar), that these inhibitory effects on IDO expression were not to of curcumin whether in IDO expression were by a in IDO activity in IFNγ-activated BMDCs, we cell for the of kynurenine, a of in a of curcumin induced a of IFNγ-induced IDO and PKCδ Tyrosine and of STAT1 in IFNγ-stimulated curcumin strongly suppressed the induction of IDO expression and activity in IFNγ-stimulated BMDCs, we to the precise mechanisms in the induction and of IDO expression by IFNγ and curcumin, We whether phosphorylation of tyrosine and serine of STAT1 regulated by and PKCδ in IFNγ-stimulated murine and STAT1 were activated in response to IFNγ, a after IFNγ with suppressed tyrosine phosphorylation of STAT1 in IFNγ-stimulated BMDCs, serine phosphorylation of STAT1 and phosphorylation of PKCδ not to whether phosphorylation of STAT1 in response to IFNγ on we BMDCs with the for with IFNγ for IFNγ-induced serine phosphorylation of STAT1 STAT1 tyrosine phosphorylation a of that and regulate the expression of genes in cell Immunol.. 18: Scholar). further the of PKCδ in IFNγ-induced IDO expression, we whether could regulate serine phosphorylation of STAT1 in response to IFNγ. which and and which were for their to inhibit STAT1 serine BMDCs were with of the for and with IFNγ for in these which not inhibit not the serine phosphorylation of of Both and PKCδ for IDO in IFNγ-stimulated the of and PKCδ on IDO induction by IFNγ, we IDO expression in IFNγ-stimulated BMDCs with the or PKCδ specific and we that IFNγ-induced IDO expression suppressed by the as in treatment with the PKCδ IDO expression in a in IFNγ-stimulated In of on IDO expression in IFNγ-stimulated BMDCs the that the of on IFNγ-induced IDO expression were we used to the PKCδ gene in of significantly IDO expression and PKCδ phosphorylation in response to IFNγ Curcumin STAT1 by IFNγ-induced of and PKCδ of IFNγ-induced IDO expression on and PKCδ phosphorylation that curcumin may IFNγ effects by inhibiting these downstream investigate the of curcumin on the phosphorylation of and we BMDCs with of curcumin for and cells with IFNγ for Curcumin treatment the phosphorylation of and PKCδ in IFNγ-stimulated BMDCs we whether the inhibitory of curcumin on and PKCδ activation suppressed the subsequent phosphorylation of curcumin significantly STAT1 phosphorylation on serine and tyrosine Curcumin the of STAT1 to the GAS of the IRF-1 in IFNγ-stimulated binding of phosphorylated STAT1 to the GAS site of the IRF-1 promoter is essential for the induction of IRF-1 gene transcription by IFNγ Jr., J.E. 1994; Scholar). STAT1 and IRF-1 the induction of IDO protein by IFNγ (16Chon S.Y. Hassanain H.H. Gupta S.L. J. Biol. Chem.. 1996; 271: 17247-17252Google Scholar). whether inhibiting or PKCδ the binding of IFNγ-activated STAT1 to the GAS site of the IRF-1 promoter and subsequent IRF-1 expression, BMDCs were with a or IFNγ In the using and we that inhibiting or PKCδ activation or the binding of IFNγ-activated STAT1 to the GAS sequence and subsequent IRF-1 expression in the of We whether curcumin treatment STAT1 binding to the IRF-1 promoter in IFNγ-stimulated BMDCs using the were with various of curcumin for IFNγ isolated and with a Ab, and the IRF-1 promoter by Curcumin treatment significantly STAT1 binding to the GAS on the promoter of the IRF-1 gene effects of curcumin were in using an In addition, that IRF-1 expression, which strongly induced in the IFNγ-stimulated BMDCs, inhibited after suppression of STAT1 binding to the GAS element Curcumin T-cell we to whether curcumin treatment could reverse IDO-mediated suppression of T-cell in a previous study of we found that curcumin a suppression of the T-cell function by the expression of Kim Lee Yoon M.S. Lee H.J. Lee C.M. Park Park Y.M. J. Immunol.. 2005; Scholar). to the expression of in IFNγ-stimulated with previous to induce the expression of and on CD11c+ cells on IFNγ not curcumin the expression of and and complex in BMDCs, has inhibitory on the expression of Kim Lee Yoon M.S. Lee H.J. Lee C.M. Park Park Y.M. J. Immunol.. 2005; Scholar). the of curcumin on IDO-mediated T-cell suppression from the of curcumin on the expression of we established system using OT-1 T-cell receptor transgenic which a specific for the complex in DCs Heath W.R. J.L. M.J. Carbone F.R. Cell.. 1994; Scholar). with IFNγ-stimulated DCs to a significantly than the with control of IFNγ reversed by treatment of DCs with a well of the proliferation potential of OT-1 cells by with DCs with curcumin IFNγ We have previously reported that the of curcumin can be to the of mitogen-activated protein kinase and in signaling and Kim Lee Yoon M.S. Lee H.J. Lee C.M. Park Park Y.M. J. Immunol.. 2005; Scholar). we demonstrate an biological property of curcumin showing that curcumin also regulates IFNγ-induced IDO, a key enzyme in T-cell suppression and the induction of immune tolerance. with this we found that curcumin reversed IDO-mediated T-cell potential to The of this study to the and mechanism of of curcumin on IDO-mediated immune is well established that signaling the JAK-STAT pathway a role in the biological effects of IFNγ, specific on the mechanisms by which IFNγ IDO expression in murine BMDCs has been We that JAK1 and JAK2 activation inhibited the STAT1 tyrosine phosphorylation and induction of IDO transcription that to IFNγ. down-regulation of PKCδ with a or through suppressed IDO expression by inhibiting but not tyrosine phosphorylation of STAT1 in IFNγ-stimulated These results that tyrosine and serine phosphorylation of STAT1 are regulated by and and demonstrate that activation of STAT1 is for IFNγ-induced IDO expression in murine The initiation of IDO gene transcription is a complex that is by the expression of a key transcriptional IRF-1, IFNγ (16Chon S.Y. Hassanain H.H. Gupta S.L. J. Biol. Chem.. 1996; 271: 17247-17252Google Scholar). The IRF-1 gene promoter a GAS which binds STAT1 IRF-1 expression is by phosphorylated STAT1 that bind to this In addition, activated STAT1 binds the GAS element of the gene promoter through an with IRF-1 D.J. T. I. Darnell J.E. Cell. 1991; 11: Scholar, K. M. G. C. A. H. T. U. S. 2007; 104: Scholar). we that of STAT1 tyrosine phosphorylation the of STAT1 to bind to the element of the IRF-1 promoter that the GAS in GAS element binding that of STAT1 phosphorylation the subsequent expression of IRF-1 as well as These that IRF-1 a role in the IFNγ-induced IDO In of the mechanism of IFNγ-induced IDO expression we are to curcumin the expression of IDO in murine BMDCs with IFNγ. we that the of IDO by curcumin is by suppression of the signaling pathway. curcumin and PKCδ thereby leading to the of STAT1 phosphorylation in STAT1 phosphorylation the of the STAT1 to bind to the IRF-1 promoter and IRF-1 expression in IFNγ-stimulated A in IRF-1 expression STAT1 and IRF-1 binding to the GAS and response element sequence of the IDO gene promoter and the initiation of IDO gene curcumin at multiple in the signaling that IFNγ-induced IDO expression has been that DCs are by IFNγ, which IDO and the pathway of tryptophan catabolism (11Fallarino F. Grohmann U. Vacca C. Bianchi R. Orabona C. Spreca A. Fioretti M.C. Puccetti P. Cell Death Differ.. 2002; 9: 1069-1077Google Scholar, R. A. M. U. D. Blood.. 2004; Scholar, C. Puccetti P. Vacca C. S. A. F. Bianchi R. E. K. A. V. Fioretti M.C. Grohmann U. Blood.. Scholar). is to that murine DCs can of T-cell this can be reversed by the of an IDO U. Bianchi R. M.L. S. F. Fioretti M.C. Puccetti P. J. Immunol.. 2000; Scholar, U. F. Bianchi R. M.L. Vacca C. Orabona C. C. Fioretti M.C. Puccetti P. J. Immunol.. 2001; Scholar, U. F. S. Bianchi R. M.L. Vacca C. A. Fioretti M.C. Puccetti P. J. Immunol.. 2001; 166: Scholar). in using OT-1 T-cell receptor transgenic we that curcumin reversed the suppression of T-cell proliferation that by IFNγ-induced IDO We that the of curcumin in IDO-mediated T-cell suppression by with the of that to IFNγ-induced IDO In a previous study on we reported that curcumin the expression of a and thereby the T-cell function of these DCs Kim Lee Yoon M.S. Lee H.J. Lee C.M. Park Park Y.M. J. Immunol.. 2005; Scholar). in the T-cell of curcumin this previous report and the present study might be to in the to which and IFNγ DCs and induced IDO In the of curcumin on the immunological responses of murine DCs may be in than IFNγ in IDO than A previous study suggested that IFNγ, LPS, can directly the of H. S. H. J. Immunol.. 1996; Scholar). LPS, but not IFNγ, can induce the expression of the and these and IFNγ to their effects on IDO induction is by previous which that IFNγ, as a IDO the transcription of the IDO gene to that are than than after (14Jung I.D. Lee C.M. Jeong Y.I. Lee J.S. Park W.S. Han J. Park Y.M. FEBS Lett.. 2007; 581: 1449-1456Google Scholar). In addition, results of IFNγ and IDO that IFNγ-induced IDO expression is closely linked to T-cell suppression R.A. J.D. 2008; Scholar). These results that IFNγ-stimulated DCs have an role that the induction of curcumin the expression of and complex in BMDCs Kim Lee Yoon M.S. Lee H.J. Lee C.M. Park Park Y.M. J. Immunol.. 2005; Scholar), the of T-cell proliferation by curcumin may have to with of IDO than as in The mechanisms underlying tolerance, which a to from immune have been and are the of active Nat. Rev. Cancer.. 2005; 5: Scholar). IDO an important role in and is a for cancer that the of A.J. E. Nat. Med.. 2005; 11: Scholar, A.J. Sharma M.D. J. Banerjee T. M. Mellor A.L. Munn D.H. Cancer Res.. 2007; Scholar). the of and IDO may be a key to the of Our into the mechanisms that IDO expression in response to IFNγ and the activities of They also a for and in the