Modulation of monocyte inflammatory response through estrogen receptor α and progesterone receptor signaling

Abstract

Ovarian hormone fluctuation has been associated to clinical status of several autoimmune conditions and the influence on inflammatory disease is under investigation. The incidence of inflammatory bowel disease is high in the West and rising in other parts of the world. Immunomodulating treatments are available but there is a need for a cheap, readily available treatment with an enhanced risk-benefit ratio. The effect of estrogen and progesterone receptor mediated signaling on the immune response of myeloid cells, such as monocytes or macrophages have been studied to some extent with varying results. In addition to ovarian hormones, selective estrogen receptor modulators have also been suggested to modulate inflammatory response of several types of immune cells. In this master´s thesis project, small interfering RNA-based receptor silencing was used to investigate the immunomodulatory effect of ERα and PGR signaling as well as to illuminate the molecular mechanism of SERM2, a novel compound. Further, the aim was to gain information for the development of hormone receptor mediated immunomodulatory treatment of autoimmune or inflammatory disease. The results indicate suppression of monocyte NF-κB activation by PGR signaling, while the ERα mediated signaling had a very varied effect. It is possible that ERα upregulation increases the proinflammatory potential of monocytes. Cytokine expression analysis of both cell line and primary monocytes exhibited modulation of inflammatory cytokines by PGR mediated signaling, which possibly could reduce the activity of Th17 cells in the gut, while the opposite could be true regarding ERα upregulation.