Progesterone and estrogen effects on inflammation and role in shaping immune cell competence
In addition to the well-known role of progesterone in reproduction, this steroid regulates important immunomodulatory functions, including reshaping the competence of immune cells and inducing potent anti-inflammatory actions. Progesterone plays a significant role in the maternal reproductive apparatus, such as immune adaptations and inducing immune tolerance that promote and sustain pregnancy.
There are several ways by which progesterone induce immunomodulatory effects (Figure 1C). These include actions in the periphery where progesterone has an effect on T cell activation and a direct role on guiding their differentiation. For example, progesterone can modulate T cell receptor signal transduction or induce tolerance. Progesterone plays also a significant role in suppression of cellular cytotoxicity. Indeed, it may block degranulation by influencing via progesterone induced blocking factor.
Intriguingly, progesterone binds to receptors in immune cells, such as natural killer cells, T cells, macrophages, and dendritic cells. It also binds non-immune cells, including epithelial and endothelial cells in the respiratory tracts where it alters cellular signaling/activity improving infections. In influenza A virus, preclinical progesterone administration decreases inflammation and promotes pulmonary repair after clearance of influenza A viruses by increasing regulatory CD39+ Th17 cells and stimulating TGF-b, IL-6, and IL-22 levels. IL-22 similarly to TGF-β can stimulate the proliferation of epithelial cells and promote repair of the damaged alveolar epithelium. Progesterone signaling through progesterone receptors stimulates the epidermal growth factor amphiregulin thereby promoting proliferation and respiratory epithelial cell repair (31). A faster recovery of the lung tissue may reduce in females the susceptibility to secondary bacterial infection. In humans, this is the primary cause of mortality after influenza A virus infection (31). This finding is substantiated by studies showing that following influenza A virus infection, the histological density of pulmonary inflammation was decreased during pregnancy. These investigators conclude that “pregnancy-associated alterations in pulmonary physiology may serve to protect females during severe influenza.” (32). Combination of estradiol with progesterone showed the strongest protective role in the lungs after the stimulation of the inflammatory cascade thereby explain a milder clinical outcome that has been observed in virus infected women in early compared with late gestation (33).
Like progesterone, estrogens are strong immune regulatory agent. Estrogens regulate immune cell responses and promote anti-inflammatory and neuroprotective effects. Increase in circulating estrogen concentration affects progenitor and mature cells of both the innate and adaptive immune systems (34).
In the innate immune system estrogens regulate the number of cells and their functions. In neutrophils, estrogens regulate chemotaxis, infiltration, as well as the induction of cytokine-induced chemoattractants and cytokines (e.g., TNF-α, IL-6, IL-1β). In dendritic cells, they stimulate the differentiation and directly regulate expression of chemokine (e.g., IL-8) and cytokine (e.g., IL-6, IL-10). In macrophages, estrogens regulate chemotaxis, phagocytic activity, and the production of cytokines (e.g., IL-6, TNF-α). Estrogens influence the phenotype of T helper cells and have profound effects on B cell maturation, differentiation, activity, and survival (34). Estradiol modulates cytokine secretion by CD4+ T cells. Intriguingly, during menopause women are at higher risk of autoimmune diseases. This decline in the content of estrogens during menopause reduces the number of B and T cells while increasing production of pro-inflammatory cytokines (36).