Differential actions of glycodelin-A on Th-1 and Th-2 cells: a paracrine mechanism that could produce the Th-2 dominant environment during pregnancy

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Cheuk-Lun Lee1,2,3,†, Philip C.N. Chiu1,3,*†, Kevin K.W. Lam1, Siu-On Siu2, Ivan K. Chu2, Riitta Koistinen4, Hannu Koistinen4, Markku Seppälä4, Kai-Fai Lee1,3 and William S.B. Yeung1,3

1Department of Obstetrics and Gynaecology, University of Hong Kong, Pokfulam Road, Hong Kong, China

2Department of Chemistry, University of Hong Kong, Pokfulam Road, Hong Kong, China

3Centre for Reproduction, Development and Growth, University of Hong Kong, Pokfulam Road, Hong Kong, China

4Department of Clinical Chemistry, Helsinki University Central Hospital and University of Helsinki, 00029 HUS Helsinki, Finland *Correspondence address. Tel: +852-28199388; Fax: +852-28161947; E-mail: pchiucn{at}hkucc.hku.hk?† Contributed equally to the report.

Received June 24, 2010. Revision received November 29, 2010. Accepted December 6, 2010. BACKGROUND The maternal–fetal interface has a unique immunological response towards the implanting placenta. It is generally accepted that a T-helper type-2 (Th-2) cytokine prevailing environment is important in pregnancy. The proportion of Th-2 cells in the peripheral blood and decidua is significantly higher in pregnant women in the first trimester than in non-pregnant women. Glycodelin-A (GdA) is a major endocrine-regulated decidual glycoprotein thought to be related to fetomaternal defence. Yet the relationship between its immunoregulatory activities and the shift towards Th-2 cytokine profile during pregnancy is unclear.

METHODS GdA was immunoaffinity purified from human amniotic fluid. T-helper, T-helper type-1 (Th-1) and Th-2 cells were isolated from the peripheral blood. The viability of these cells was studied by XTT assay. Immunophenotyping of CD4/CD294, cell death and GdA-binding were determined by flow cytometry. The mRNA expression, surface expression and secretion of Fas/Fas ligand (FasL) were determined by quantitative polymerase chain reaction, flow cytometry and ELISA, respectively. The activities of caspase-3, -8 and -9 were measured. The phosphorylation of extracellular signal-regulated kinases (ERK), p38 and, c-Jun N-terminal kinase was determined by western blotting.

RESULTS Although GdA bound to both Th-1 and Th-2 cells, it had differential actions on the two cell-types. GdA induced cell death of the Th-1 cells but not the Th-2 cells. The cell death was mediated through activation of caspase -3, -8 and -9 activities. GdA up-regulated the expression of Fas and inhibited ERK activation in the Th-1 cells, which might enhance the vulnerability of the cells to cell death caused by a trophoblast-derived FasL.

CONCLUSIONS The data suggest that GdA could be an endometrial factor that contributes to the Th-2/Th-1 shift during pregnancy.

© The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This ArticleHum. Reprod. (2011) 26 (3): 517-526. doi: 10.1093/humrep/deq381 First published online: January 11, 2011

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