title: Toll-like receptor-3 ligation-induced indoleamine 2, 3-dioxygenase expression in human trophoblasts.
abstract: Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades an essential amino acid, tryptophan, and plays a role in inhibiting the proliferation of T cells and intracellular pathogens. Inhibiting IDO in mice leads to fetal rejection, suggesting its significance in establishing pregnancy. Toll-like receptor 3 (TLR-3) is a key component of the innate immune system that recognizes viral double-stranded RNA and triggers immune reactions by producing type I interferon. Using a human trophoblast cell culture system, we studied the effect of TLR-3 ligation on IDO expression and function by treating trophoblasts with polyinosinic-polycytidylic acid [poly(I:C)] (a synthetic double stranded RNA, which mimics viral RNA). Real-time PCR and Western blot analysis revealed that IDO mRNA and protein expression was significantly induced by poly(I:C). The activity of IDO was also increased by poly(I:C) given that the L-kynurenine concentrations were elevated in conditioned media. Conditioned media from poly(I:C)-treated trophoblasts were found to inhibit the proliferation of human T cells significantly. Poly(I:C) was also shown to induce interferon (IFN)-β mRNA expression in trophoblasts. Recombinant human IFN-β increased IDO mRNA expression in trophoblasts more rapidly than poly(I:C). Pretreating with neutralizing antibody against IFN-β significantly suppressed IDO induction by poly(I:C). Collectively we have demonstrated that ligation of TLR-3 by poly(I:C) induces IDO expression in human first-trimester trophoblasts via an IFN-β-dependent pathway. These findings suggest that upon viral infection, trophoblasts induce IDO and in turn contribute to antimicrobial activity and maintenance of fetomaternal tolerance.
authors.affiliation: Department of Obstetrics and Gynecology, University of Tokyo, 7-3-1 Hongo Bunkyo Tokyo, 113-8655, Japan.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Kaori
authors.initials: K
authors.lastname: Koga
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cardenas
authors.forename: Gentaro
authors.initials: G
authors.lastname: Izumi
authors.forename: Masashi
authors.initials: M
authors.lastname: Takamura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hirata
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshino
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hirota
authors.forename: Miyuki
authors.initials: M
authors.lastname: Harada
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taketani
mesh_terms: D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D016899:Interferon-beta / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000276:immunology; D012327:RNA Virus Infections; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D015533:Transcriptional Activation; D014327:Trophoblasts / Q000276:immunology / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D011070:Poly I-C