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).