Obstet Gynecol Sci.  2013 Jul;56(4):209-216.

The role of placental indoleamine 2,3-dioxygenase in human pregnancy

• Kudo Y

Abstract

Munn et al. made a scientific observation of major biological importance. For the first time they showed that in the mammal the fetus does survive an immune attack mounted by the mother, and that the mechanism responsible for the survival depends on the fetus and placenta 'actively' defending itself from attack by maternal T cells by means of an enzyme indoleamine 2,3-dioxygenase (EC 1.13.11.42) dependent localised depletion of L-tryptophan. These findings raise critical questions for disease and its prevention during human pregnancy. Specifically, the role of this mechanism (discovered in mouse) in the human, and the extent to which defective activation of this process is responsible for major clinical diseases are unknown. Therefore some key facts about this enzyme expressed in the human placenta have been studied in order to test whether Munn et al.'s findings in mouse are met for human pregnancy. This short review attempts to describe our experimental work on human placental indoleamine 2,3-dioxygenase.

Keyword

Human placenta; Indoleamine 2,3-dioxygenase; Pre-eclampsia; Pregnancy; Tryptophan

MeSH Terms

Animals
Fetus
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Mammals
Mice
Mothers
Placenta
Pre-Eclampsia
Pregnancy
T-Lymphocytes
Tryptophan
Indoleamine-Pyrrole 2,3,-Dioxygenase
Tryptophan

Figure

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  Fig. 1 Effect of 1-methyl-tryptophan on indoleamine 2,3-dioxygenase activity [21]. The rate of formation of the product catalysed by indoleamine 2,3-dioxygenase was determined over a 30 minutes period in a medium containing varying concentrations of 1-methyl-DL-tryptophan, 20 mM ascorbic acid, 10 µM methylene blue, 100 units mL-1 catalase and 50 mM potassium phosphate buffer (pH 6.5) in the presence of indicated concentrations of L-tryptophan. 1-Methyl-DL-tryptophan: •, 0 µM; ○, 40 µM; ▼, 200 µM; ▽, 400 µM. Inset is a replot for the apparent Km value (Kmapp) the inhibitor concentrations used to determined the Ki value; the line was determined by least-squares linear regression analysis. Data represent the mean±standard deviation of three separate experiments with triplicate assays.

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  Fig. 2 Effect of interferon-γ (IFN-γ) on the stimulation of indoleamine 2,3-dioxygenase activity in cultured chorionic villi (From Kudo, et al. Mol Hum Reprod 2000;6:369-74, Oxford University Press [24]). Pieces of chorionic villi were cultured for the time indicated with 1,000 unit mL-1 IFN-γ or vehicle (phosphate-buffered saline) (A). Pieces of chorionic villi were cultured for 36 hours with the indicated concentrations of IFN-γ (B). Indoleamine 2,3-dioxygenase activity in tissue extract was determined. Data represent the mean±standard deviation of three separate experiments performed with three placentae.

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  Fig. 3 Effect of interferon (IFN)-γ and 1-methyl-tryptophan on tryptophan catabolism by indoleamine 2,3-dioxygenase in placental explants [25]. Villous explants were cultured with or without 1,000 unit mL-1 IFN-γ and/or 2 mM 1-methyl-tryptophan (1-Met-Trp) or vehicle (Nil) for 36 hours. Concentrations of tryptophan (A) and kynurenine (B) in the conditioned medium were analysed by high-performance liquid chromatography. Values are mean±standard deviation of five separate experiments with triplicate assay from five different samples. Control, values without culture; ND, not detectable. a)Significantly different from Nil; b)Significantly different from IFN-γ.

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  Fig. 4 Peripheral blood mononuclear cell proliferation in medium previously conditioned by culture with villous explants [26]. Peripheral blood mononuclear cells were cultured for 72 hours either in non-conditioned medium or in medium previously conditioned by culture of explants with 1,000 unit mL-1 interferon-γ (IFN) and/or 2 mM 1-methyl-tryptophan (1-Met-Trp) for 36 hours. [3H]thymidine incorporation was then determined. Data represent the standard deviation of five separate experiments with quadruplicate assay, expressed as percentage of control (i.e., values cultured in non-conditioned medium). Control value for [3H]thymidine incorporation into DNA is (5.93±0.34)×104 cpm/well. Nil, vehicle. a)Significantly different from Nil; b)Significantly different from IFN-γ.

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