11ß-HSD1: novel roles and implications in pathology and physiology of reproduction and in skin homeostasis

My three-years work focused on the enzyme 11B-HSD1 and its implications and roles in human reproduction and skin homeostasis. The enzyme is involved in the local regulation of glucocorticoids availability, being responsible of the cortisone activation to cortisol. My project was composed of three major parts. In the first section, I analyzed the role of the enzyme in the human first trimester decidua. My experiments included a global evaluation of the enzyme susceptibility to respond to hormonal and cytokine stimuli, driving the first part of pregnancy. Our findings reported that 11B-HSD1 expression and activity are stimulated by a combined treatment of estradiol and medroxyprogesterone (used as analogue of progesterone). In parallel experiments, we demonstrated that also interleukin 1, alone and in combination with interferon-, has the ability to increase expression and activity of the enzyme. In the same work, that resulted in a paper published on Molecular and Cellular Endocrinology, we reported that elevated expression levels of 11B-HSD1 in decidua correlated with development of preeclampsia, suggesting a possible implication of the enzyme also in a pathological onset. In the second section, I investigated the role of 11B-HSD1 in the second part of gestation, using a dual-model approach involving murine and human uterus. We demonstrated the close correlation between pregnancy progression and 11B-HSD1 expression levels. In particular, after an early stable state, we observed a progressive increase of the mRNA and protein expression of the enzyme from mid-pregnancy to the last day of murine pregnancy, followed by an expression drop at the onset of labour. Our experiments with human cells reported also that 11B-HSD1 is involved in myometrium contraction, suggesting that enzyme has an essential role also in the mechanism of labour. In the last part of my thesis, I explored the skin pathology of psoriasis and one of its possible medical treatments, narrow-band UVB irradiation. In our preliminary experiments, we studied the expression levels of 11B-HSD1 before and after this medical approach on psoriatic patients, comparing results with control subjects. Our findings showed that controls and patients before the treatments have similar 11B-HSD1 expression levels. After the treatment period, mRNA and protein expression of the enzyme significantly rose up, suggesting a possible involvement of the 11-HSD1 in the molecular mechanism of the symptoms improvement. Globally, we reported a new vision of 11B-HSD1, with involvement in physiology and pathology of gestation and skin, never observed in previous reports, highlighting new perspectives in roles and ‘specific weight’ of the enzyme in organs and tissues different from the classic targets of 11B-HSD1.