Mechanisms regulating the expression of indoleamine 2,3-dioxygenase during decidualization of human endometrium

A. Honig, L. Rieger, J. Dietl and U. Kämmerer

Department of Obstetrics and Gynaecology, University of Würzburg, Josef-Schneider str. 4, D-97080 Wuerzburg, Germany

Email: frak057{at}mail.uni-wuerzburg.de

Sir,

The recent interesting work of Kudo et al. (2004)Go prompted us to comment on the presented data regarding indoleamine 2,3-dioxygenase (IDO) expression. The authors performed an investigation evaluating IDO mRNA levels in non-pregnant endometrium, decidua as well as in decidualized endometrium from ectopic pregnancies.

Using RT–PCR, the authors found IDO mRNA expression to be higher during decidualization of human endometrium as compared with non-pregnant endometrium, which may point to a possible significance of IDO for gestation. The authors suggest that the measured mRNA results from decidual stromal cells, but they do not describe the purification of stromal cells prior to RNA extraction. Endometrial samples always consist of a mixture of cells including a variety of immune cells (Starkey et al., 1991Go). IDO is known to be expressed in immune cells, such as activated dendritic cells (Hwu et al., 2000Go). These cells can be found both in endometrium and in decidua, and therefore it is difficult to determine whether the detected IDO mRNA originates from immune cells or from stromal cells. The experiments were not designed to discriminate which cell type is the source of IDO expression.

Some of the immunohistochemical results of Kudo et al. (2004)Go may raise doubts. We evaluated the monoclonal and polyclonal antibodies by Chemicon as well as the monoclonal antibody used by Kudo et al. The polyclonal antibody was first described by Munn et al. (2002)Go who demonstrated its application in immunohistochemistry. When testing the monoclonal antibody as used by Kudo et al., we achieved results which resembled those which are presented in their paper. It was mainly the cells with high concentrations of Fc-receptors that have the capacity to bind antibodies unspecifically on their surface, such as syncytiotrophoblast, endothelia and mast cells which were stained positive. In contrast, the use of the polyclonal antibody led to clear and reproducible staining results. We mainly found specific IDO expression in the extravillous trophoblast (Honig et al., 2004Go).

On account of the contradictory results obtained with the two antibodies, we compared their ability to detect IDO in interferon-{gamma} (IFN-{gamma})-stimulated mature dendritic cells, which are known to express this enzyme extensively (Hwu et al., 2000Go). While reliable results in terms of IDO detection were gained with the polyclonal antibody, the monoclonal antibody only led to a faint staining of the cells.

Furthermore, Kudo et al. (2004)Go used a secondary antibody system that usually enhances the signal. This enhancement is caused by the multiple phosphatases bound to the secondary antibody which lead to rather strong signals. When taking that into consideration, the visualization in the presented immunohistochemical figures appears rather weak.

The authors describe two opposing factors that influence IDO expression. IFN-{gamma} stimulates and progesterone suppresses IDO expression. Drawing conclusions from a cell culture system for the decidualization in vivo is difficult. Levels of IFN-{gamma} and progesterone might not be the same, and other factors for IDO regulation could be missing (Carlin et al., 1987Go).

As IDO has been gaining increasing scientific attention, future experiments might show how significant its expression is for human gestation.

References

Carlin JM, Borden EC, Sondel PM and Byrne GI (1987) Biologic-response-modifier-induced indoleamine 2,3-dioxygenase activity in human peripheral blood mononuclear cell cultures. J Immunol 139, 2414–2418.[Abstract/Free Full Text]

Honig A, Rieger L, Kapp M, Sütterlin M, Dietl J and Kämmerer U (2004) Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance. J Reprod Immunol 61, 79–86.[CrossRef][ISI][Medline]

Hwu P, Du MX, Lapointe R, Do M, Taylor MW and Young HA (2000) Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibtion of T cell proliferation. J Immunol 164, 3596–3599.[Abstract/Free Full Text]

Kudo Y, Hara T, Katsuki T, Toyofuku A, Katsura Y, Takikawa O, Fujii T and Ohama K (2004) Mechanisms regulating the expression of indoleamine 2,3-dioxygenase during decidualization of human endometrium. Hum Reprod 19, 1222–1230.[Abstract/Free Full Text]

Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, Marshall B, Chandler P, Antonia SJ, Burgess R, Slingluff CL Jr and Mellor AL (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297, 1867–1870.[Abstract/Free Full Text]

Starkey PM, Clover LM and Rees MC (1991) Variation during the menstrual cycle of immune cell populations in human endometrium. Eur J Obstet Gynecol Reprod Biol. 39, 203–207.[ISI][Medline]





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