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Modulates Prolactin and Tissue Factor Expression in Differentiating Human Endometrial Stromal Cells1
Institute of Reproductive and Developmental Biology, Imperial College School of Medicine, and Medical Research Council Clinical Sciences Center (J.M.), Hammersmith Hospital, London, United Kingdom W12 ONN; and Department of Pathology, Hillingdon Hospital (F.B.), London, United Kingdom UB8 3NN
Address all correspondence and requests for reprints to: Dr. Jan Brosens, Institute of Reproductive and Developmental Biology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, United Kingdom W12 ONN. E-mail: j.brosens{at}ic.ac.uk
Cytokines such as interferon-
(IFN) released by resident uterine
immune cells are thought to influence the expression of differentiated
function in the human endometrium. Decidualization of the stromal cell
compartment is confined to the superficial endometrial layer in the
nonpregnant uterus. To explore the molecular mechanism underlying the
spatial expression of the decidual phenotype, the effect of IFN on
the induction of two well characterized markers of endometrial stromal
(ES) cell differentiation, PRL and tissue factor (TF), has been
investigated. IFN antagonizes cAMP-mediated PRL protein and
messenger RNA expression in primary ES cell cultures through inhibition
of decidual PRL promoter activity. In parallel, IFN stimulates
Stat-1 (signal transducer and activator of transcription-1) expression,
phosphorylation, and translocation to the nucleus. Exogenously
expressed Stat-1 potently represses decidual PRL promoter activation,
indicating the potential for the inhibitory effects of IFN to be
mediated by Stat-1. We demonstrate that although the coactivator
CREB-binding protein/p300 is essential for decidual PRL transcription,
this coactivator does not appear to be the target for IFN-mediated
repression. By contrast, IFN has little effect on cAMP-mediated TF
expression, but induces TF in ES cells not exposed to a decidualizing
stimulus. This suggested that in vivo TF expression may
not be restricted to decidualizing cells of the superficial layer and
was confirmed by imunohistochemical analysis demonstrating intense TF
staining in the basal stromal compartment during the regeneration phase
of the cycle. The differential sensitivity of
decidualization-associated genes to IFN illustrates its potential
role as a selective biological response modifier that influences
regional function within the endometrium.
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