Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells.
Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-gamma (IFNgamma)-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 IFNgamma, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFNgamma-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 IFNgamma. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase Cdelta 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 IFNgamma-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.
Jeong
Young-Il
YI
Department of Microbiology, College of Natural Science, Pusan National University, Geumjeong-Gu, Busan 609-735, Korea.
Kim
Sang Woo
SW
Jung
In Duk
ID
Lee
Jun Sik
JS
Chang
Jeong Hyun
JH
Lee
Chang-Min
CM
Chun
Sung Hak
SH
Yoon
Man-Soo
MS
Kim
Geun Tae
GT
Ryu
Seok Woo
SW
Kim
Jong-Suk
JS
Shin
Yong Kyoo
YK
Lee
Won Suk
WS
Shin
Hwa Kyoung
HK
Lee
Jae-Dong
JD
Park
Yeong-Min
YM
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology; D002467:Cell Nucleus / Q000201:enzymology / Q000276:immunology; D028462:Cucumis / Q000276:immunology; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects / Q000502:physiology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000276:immunology; D050856:Interferon Regulatory Factor-1 / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000276:immunology / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000201:enzymology / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D051745:Protein Kinase C-delta / Q000276:immunology / Q000378:metabolism*; D020218:Response Elements / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050856:Interferon Regulatory Factor-1; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051745:Protein Kinase C-delta