Decidual Cells Produce a Heparin-binding Prolactin Family Cytokine with Putative Intrauterine Regulatory Actions

Abstract

Pregnancy in mice and rats is associated with the production of a large family of hormones/cytokines related to prolactin (PRL). The hormones/cytokines are hypothesized to coordinate maternal and fetal adaptations to pregnancy. In this study, PRLlike protein-J (PLP-J, also known as PRL family 3, subfamily c, member 1 (Prl3c1)) is shown to be a product of the uterine decidua and a regulator of postimplantation intrauterine events. PLP-J-specific antibodies and a series of recombinant PLP-J proteins were generated and used to investigate PLP-J expression and as ligands for investigating biological targets. Decidual PLP-J migrates as a 29-kDa protein and localizes to a band of decidual cells surrounding the trophoblast cell layer on gestation day 8.5. PLP-J ligands specifically bound in situ to the surrounding uterine stromal cells and vasculature within the decidua of gestation day 8.5 implantation sites. We then investigated the in vitro actions of PLP-J on uterine stromal cells and endothelial cells. PLP-J specifically interacted with both cell populations. PLP-J promoted uterine stromal cell proliferation and inhibited endothelial cell proliferation. We determined that PLP-J does not interact with PRL receptors. Instead, PLP-J interacts with heparin-containing molecules, including syndecan-1, which is expressed in gestation day 8.5 pregnant uteri, as well as in uterine stromal cells and endothelial cells. The restricted expression of PLP-J and its specific interactions with uterine stromal cells and endothelial cells suggests that it acts locally and regulates decidual cell development and the endometrial vasculature.Successful pregnancy requires specialized maternal adaptations. Decidualization is a key uterine adaptation associated with the establishment of pregnancy and is characterized by the differentiation of uterine stromal cells (1-4). Decidual cell differentiation is dependent upon ovarian steroid hormone production, and in rodents, it also requires signals emanating from the preimplantation embryo (1, 5). Once formed, decidual cells establish a protective environment, facilitating the development of the placenta and embryo. They promote the redistribution of specific populations of leukocytes and reorganize the uterine vascular network. Intercellular signals elaborated by decidual cells are key mediators of these uterine adaptive responses. Among the decidual cell ligands are a family of cytokines related to prolactin (PRL). 2PRL is an ancient hormone with its origins as a regulator of vertebrate environmental adaptations (6, 7). Some species possess a single member of the PRL family that can be expressed in an assortment of tissues, including the anterior pituitary and uterus through the utilization of cell-specific promoters (8 -10). Other species have undergone a gene expansion within the PRL locus (11). PRL family gene expansion is particularly robust in mice and rats (12)(13)(14). Gene duplication and natural selection have yielded 2 dozen related genes in each of these species. The PRL family ge...

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions

“…Our recent proteomics analysis found downregulation of a decidua-enriched prolactin-like hormone, prolactin-like protein J (PLP-J), in Trp53 loxP/loxP Pgr Cre/+ deciduae (24). PLP-J was identified in rat decidua and is implicated in maintaining decidual cell survival (25)(26)(27)(28). Our in situ hybridization results show that Prl3c1, encoding PLP-J, was highly expressed in the decidua surrounding the developing embryo on day 8 in Trp53 loxP/loxP Pgr +/+ females but was markedly downregulated in Trp53 loxP/loxP Pgr Cre/+ deciduae, consistent with our previous proteomics results ( Figure 2A).…”

Placental ischemia induces changes in gene expression in chorionic tissue

“…Despite this difference, there is a clear and consistent widespread upregulation of a diverse array of these genes, pointing to a common mechanism of regulation in response to placental ischemia. Interestingly, a correlation between preeclampsia and increased prolactin expression was noted as early as the 1970s, and extensive characterization by the Soares laboratory has demonstrated differential temporal and tissue regional localization of a number of these transcripts in the placenta during pregnancy (Ain et al 2003; Alam et al 2008; Orwig and Soares 1999; Redman et al 1975; Soares et al 2007; Wang et al 2000; Wiemers et al 2003). Several recent studies have indicated a link between preeclampsia and elevated prolactin.…”

Prolactin Family of the Guinea Pig, Cavia porcellus

“…Guinea pig flag-tagged PRL and PRLRP1 were identified with anti-FLAG M2 antibodies (Sigma-Aldrich) and visualized by enhanced chemiluminescence according to the manufacturer's instructions (Amersham Biosciences, Piscataway, NJ). Flag-tagged rat PRL-like protein-J (PLP-J) (32) and mock-transfected HEK-293 cells were used as positive and negative controls, respectively.…”