Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

Abstract

The specific regulation of inflammatory processes by steroid hormones has been actively studied in recent years, especially by progesterone (P4) and progestins. The mechanisms of the anti-inflammatory and immunomodulatory P4 action are not fully clear. The anti-inflammatory effects of P4 can be defined as nonspecific, associated with the inhibition of NF-κB and COX, as well as the inhibition of prostaglandin synthesis, or as specific, associated with the regulation of T-cell activation, the regulation of the production of pro- and anti-inflammatory cytokines, and the phenomenon of immune tolerance. The specific anti-inflammatory effects of P4 and its derivatives (progestins) can also include the inhibition of proliferative signaling pathways and the antagonistic action against estrogen receptor beta-mediated signaling as a proinflammatory and mitogenic factor. The anti-inflammatory action of P4 is accomplished through the participation of progesterone receptor (PR) chaperones HSP90, as well as immunophilins FKBP51 and FKBP52, which are the validated targets of clinically approved immunosuppressive drugs. The immunomodulatory and anti-inflammatory effects of HSP90 inhibitors, tacrolimus and cyclosporine, are manifested, among other factors, due to their participation in the formation of an active ligand–receptor complex of P4 and their interaction with its constituent immunophilins. Pharmacological agents such as HSP90 inhibitors can restore the lost anti-inflammatory effect of glucocorticoids and P4 in chronic inflammatory and autoimmune diseases. By regulating the activity of FKBP51 and FKBP52, it is possible to increase or decrease hormonal signaling, as well as restore it during the development of hormone resistance. The combined action of immunophilin suppressors with steroid hormones may be a promising strategy in the treatment of chronic inflammatory and autoimmune diseases, including endometriosis, stress-related disorders, rheumatoid arthritis, and miscarriages. Presumably, the hormone receptor- and immunophilin-targeted drugs may act synergistically, allowing for a lower dose of each.

Downregulation of pattern recognition receptors on macrophages involved in aggravation of endometriosis

“…However, several studies have revealed the immunomodulatory effects of progesterone and progestin in the female genital tract and immune system. 56,57 Progesterone treatment tilts the Th1/Th2 balance toward Th2 58,59 and inhibits DC differentiation 60 In addition, we found that progesterone treatment prevents murine miscarriage via the suppression of IL-12 production by macrophages (manuscript in preparation). Therefore, we believe that progestins have no effect on surface markers or alamin production in our study; however, they may cause functional changes such as cytokine production in macrophages and other immune cells.…”

New insights on the potential effect of progesterone in Covid‐19: Anti‐inflammatory and immunosuppressive effects

“…P4 activated an inhibitory G‐protein suggesting that mPRs are coupled to inhibitory G‐protein in Jurkat cells. These results suggest a potential novel mechanism for P4 immunoregulatory function through activation of mPRs 26,27 . P4‐induced blocking factor (PIBF) is a protein secreted by lymphocytes exposed to P4.…”

“…Variation in the expression of mPRs may influence P4 regulatory performance during pregnancy. PIBF increases in pregnant normal women compared to women who have experienced abortion 26,27 . P4 inhibits innate immune response by suppressing the activity of dendritic cells and macrophages by inhibiting the release of pro‐inflammatory cytokines by interfering with nuclear factor kappa B (NF‐κB) 28 .…”

Setting a stage: Inflammation during preeclampsia and postpartum

“…This inflammatory phenotype may in part be due to the progressive decrease in circulating progesterone and Progesterone Induced Blocking Factor (PIBF) that occurs as normal pregnancies progress to parturition (Polgar et al, 2004;Hudic et al, 2016). Progesterone and PIBF both inhibit lymphocyte proliferation and inflammatory cytokine production, which potentially implicates them as important anti-inflammatory agents in the earlier portion of the pregnancy (Fedotcheva et al, 2022). Near the 37th week of pregnancy, PIBF decreases triggering increases in IL-1β and IL-6 along with decreases in the anti-inflammatory cytokines IL-1Ra and IL-9 (Polgar et al, 2004;Jarmund et al, 2021).…”