Indoleamine 2,3‐Dioxygenase Expression in Monocytes of Healthy Nonpregnant Women After Induction with Human Choriongonadotropine

Abstract

The interferon-g (IFN-g)-induced enzyme indoleamine 2,3-dioxygenase (IDO) is discussed to play an important role in the induction of allogeneic immune tolerance in pregnant women. IDO is expressed in human placenta and in certain macrophages that affects the suppression of T-cell activity by catabolizing the essential amino acid L-tryptophan [1]. Indeed, during pregnancy, the systemic plasma tryptophan concentration falls significantly [2]. Moreover, T-cell proliferation could be inhibited by macrophage tryptophan catabolism as demonstrated by Munn et al. [3] But it is still not clear how allogeneic T-cell tolerance in pregnancy may be achieved by this mechanism.In a previous study, we have shown a spontaneous IDO expression in monocytes of healthy pregnant women by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in contrast to nonpregnant healthy volunteers [4]. Up to date, it is not clear why pregnant women have this spontaneous IDO expression. An increased expression of IFN-g does not seem to induce IDO, because IFN-g is one of the cytokines that are significantly decreased in the decidua of healthy pregnant women [5].Here we analysed the most upregulated hormones in pregnancy for their ability to induce IDO. The IDO expression induced by the hormones human choriongonadotropine (b-HCG), oestrogen and progesterone in monocytes derived of the peripheral blood of six healthy nonpregnant women was assessed by a quantitative real-time RT-PCR and compared to the spontaneous and IFN-g-induced IDO expression. The median age of the examined healthy nonpregnant women was at 35 years (range 24-43 years), two of the six women had previous pregnancies. The monocytes isolated from whole blood were incubated for 24 h (37 C, 5% CO 2 ) with 1500 IU b-HCG, 1.4-mg oestrogen and 20-mg progesterone.Real-time RT-PCR was performed using the Lightcycler (Roche Diagnostics, Mannheim, Germany) with the forward primer 5 0 -ACAGACCACAAGTCACAGCG and the reverse primer 5 0 -AACTGAGCAGCATGTCCTCC and the hybridization probes GCAGTGCAGGCCAAAG-CAGCGTCTTTCAGTGCTTT-X and LC Red640-ACGTCCTTGCTGGGCATCCA. The expression of IDO transcript was determined and normalized using the glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-housekeeping gene as an endogenous reference with the primers 5 0 -TTCACCACCATGGAGAAGGCT and 5 0 -ATGGCATGGACTGTGGTCATG and the probes ATCATCAGCAATGCCTCCTGCACCACCAACTGCT-X and LC Red640-AGCACCCCTGGCCAAGGTCATC-CAT-ph. All analyses were performed in duplicate.Here we describe for the first time that IDO was expressed in the monocytes of all the six nonpregnant healthy volunteers after the induction of the above hormones. Interestingly, the b-HCG-induced IDO expression was the highest with 117% at median (range 27.9-609.7%), which was quit comparable to the IFN-g-induced IDO expression with a median at 109.7% (range 35.7-301.4%). Further, we also found an IDO expression after stimulation with oestrogen and progesterone, which was lower as the IFN-g-and b-HCG-induced IDO expression. The median of the oestrogen-...

The Role of Placental Tryptophan Catabolism

“…Also hormones such as estrogen (32) and human chorionic gonadotropin (hCG) (33–35) induce IDO1 expression. Upregulation of IDO1 in DC by hCG is independent of IFN-γ (34).…”

Human chorionic gonadotropin and indolamine 2,3-dioxygenase in patients with GVHD

“…3 An immunosuppressive effect inducible by hCG has previously been demonstrated for IDO, in maternal-fetal acceptance, autoimmunity and GVHD. [4][5][6][7] Further, IL10 and Tregs are also known factors to induce tolerance in the transplant setting. [4][5][6][7] Therefore, given the low rate of adverse effects, we off-label used low dose of hCG to treat 20 patients as fourth-or fifth-line therapy with steroid-refractory or intolerant severe-grade chronic GVHD.…”

Expression von Indolamin 2,3-dioxygenase in der Plazenta

“…IL-4, IL-13 and nitric oxide inhibit expression of IDO [8,9]. Hormones contribute to the regulation of IDO: human chorionic gonadotropine (hCG), estrogen and progesterone induce IDO [10,11]. Locations of high enzyme activity include the placenta, the lung and the small intestine [12].…”