Cell-cell adhesion and cadherin expression in the GH\sb3 somatolactotrope cell line: Implications for prolactin gene expression

Expression of the prolactin gene by lactotropes of the anterior pituitary is modulated by interactions with other lactotropes, with gonadotropes, and with folliculo-stellate cells. However, little is known about which cell-cell adhesion molecules mediate these interactions. We utilized the GH\sb3 rat anterior pituitary cell line as a model system in which to examine the expression and function of anterior pituitary cell-cell adhesion molecules. Extracellular CaCl\sb2 induces prolactin mRNA levels by 5-10 fold in GH\sb3 cells and causes a striking induction of cell-cell adhesion, raising the possibility that the two events are causally linked. Time course experiments indicated the onset of prolactin mRNA always occurred after the onset of cell-cell adhesion and required voltage sensitive calcium channels. Both heparin and trypsin blocked cell-cell adhesion and the prolactin mRNA induction without affecting the levels of other mRNAs. Based on these data we propose a role for both voltage-sensitive calcium channels and calcium-dependent cell-cell adhesion in the CaCl\sb2 induction of prolactin gene expression. Cadherins may mediate GH\sb3 cell-cell adhesion based on the observation of adherens junctions between GH\sb3 cells. Experiments were inconclusive which used cadherin-specific blocking agents such as N-cadherin antisense oligonucleotides and an N-cadherin blocking antibody in attempts to block the calcium-dependent induction of cell-cell adhesion and prolactin mRNA. This raised the possibility that multiple cadherins and/or other cell-cell adhesion molecules were expressed in GH\sb3 cells and contributed to calcium-dependent cell-cell adhesion as well. Studies supporting this hypothesis indicated that N-cadherin, R-cadherin, and cadherin-9 were expressed in GH3 cells. All three mRNAs were induced by cycloheximide, indicating that they may be regulated at the level of mRNA stability. N-cadherin transcripts were detected in male and cycling female adult rat anterior pituitaries, but were downregulated in anterior pituitaries from pregnant rats. These studies raise the possibility that cell-cell adhesion and cadherin expression plays a functional role in the regulation of the lactotrope phenotype.

Sex hormone regulation of innate immunity in the female reproductive tract : the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens

The immune system in the female reproductive tract (FRT) does not mount an attack against HIV or other sexually transmitted infections (STI) with a single endogenously produced microbicide or with a single arm of the immune system. Instead, the body deploys dozens of innate antimicrobials to the secretions of the female reproductive tract. Working together, these antimicrobials along with mucosal antibodies attack many different viral, bacterial and fungal targets. Within the FRT, the unique challenges of protection against sexually transmitted pathogens coupled with the need to sustain the development of an allogeneic fetus have evolved in such a way that sex hormones precisely regulate immune function to accomplish both tasks. The studies presented in this review demonstrate that estradiol and progesterone secreted during the menstrual cycle act both directly and indirectly on epithelial cells and other immune cells in the reproductive tract to modify immune function in a way that is unique to specific sites throughout the FRT. As presented in this review, studies from our laboratory and others demonstrate that the innate immune response is under hormonal control, varies with the stage of the menstrual cycle, and as such is suppressed at mid-cycle to optimize conditions for successful fertilization and pregnancy. In doing so, a window of STI vulnerability is created during which potential pathogens including HIV enter the reproductive tract to infect host targets