Glucocorticoids are essential endocrine regulators of body functions in homeostasis and adaptation to environmental changes. One important feature of GCs regulation is the circadian control of GCs secretion by the HPA axis. The rhythmically released GCs may have an impact on immunity regulation (10). Endogenous GCs act on a variety of cell types to regulate the expression of genes controlling cellular metabolism, growth, differentiation, and apoptosis (11, 12). Thus, proper production and activity of the endogenous GCs is critical for the regulation of inflammatory events during tissue repair and pathogens elimination. Due to their potent immune-suppressive and anti-inflammatory function, synthetic GCs are extensively used in clinic to treat acute and chronic inflammation (13, 14).

The GCs act via genomic (transcriptional) and non-genomic (transcription-independent) mechanisms. Most cellular actions of GCs are mediated by binding to its cognate intracellular receptor (GR), transcription factor of the nuclear receptors (NR) superfamily (15). GR shares functional domains with other NR that include an N-terminal transactivation domain, a highly conserved central DNA binding domain, and a C-terminal ligand-binding domain (11). After ligand-induced conformational changes, GR translocates into the nucleus where it regulates transcription of hundreds of genes. It may bind directly to DNA via glucocorticoid recognition elements, or regulate gene expression via indirect mechanisms (16, 17). GR may directly interact with NF-κB (17, 18), a key transcription factor that activates many pro-inflammatory genes (19), as well as with other transcription factors (TFs), such as STAT-3 and -5 (20, 21), AP-1 (22), and CREB (23). GR does not interfere with the DNA binding activity of NF-κB, but inhibits its transcriptional activation function via preventing its nuclear translocation (17, 18), or interfering with transcriptional machinery by competition with co-factors such as p300/CBP (24), thus repressing the expression of pro-inflammatory genes, such as TNF-α, IL-1, and ICAM-1 (13, 25). Mechanisms of GCs actions also include induction of proteins with anti-inflammatory activities, such as glucocorticoid-induced leucine zipper (GILZ) (26, 27), which mediates many of the GCs’ activities (28–31), including inhibition of RAS/RAF/MAPK pathways (32, 33), and of NF-κB and AP-1 activities (34–37). “Non-genomic” effects of GCs include direct interaction of liganded GR with diverse intracellular mediators and modulating several signaling pathways, including protein kinase C, phosphatidylinositol-specific phospholipase C, and src kinase pathways (38–42).

Sex hormones regulate reproductive and metabolic body functions throughout the life of the subjects. Sex hormones influence immune cell function and inflammation: androgens are mainly anti-inflammatory (7), whereas estrogens have both pro- and anti-inflammatory roles, depending on several factors, such as type of immune response or variability of expression of different estrogen receptor (ER) isoforms (8).

Estrogens exert their effects through binding to ERα or ERβ, TFs of NR superfamily that regulate expression of genes involved in cell survival, proliferation, differentiation, and reproductive functions (6, 43). Similar to GR, nuclear ERs bind DNA either directly through estrogen response elements, or indirectly, via ERE-independent TFs, such as NF-κB, SP1, AP-1, C/EBPβ (43–45), to induce or repress gene expression. Estrogens also elicit rapid (“non-genomic”) signal transduction effects, via modulation of intracellular calcium, cAMP, potassium currents, phospholipase C activation, and stimulation of PI3K/AKT and ERK pathways (44).

Estrogen receptors are expressed in various types of immune cells, including lymphocytes, macrophages, and dendritic cells (DC) (5, 8). Estrogens were shown to exert both, anti- and pro-inflammatory effects, depending on the context and combination of factors that include: the type of the immune cell target, the concentration of the hormone, the type of immune stimulus (foreign or auto-antigens), the target organ microenvironment, and the relative expression of ERα and ERβ. Estrogens may promote inflammation via regulation of the expression of inflammatory mediators via Akt/mTOR pathway (46, 47). However, pregnancy or higher doses of ectopic estrogens typically suppress immune responses (4), by repressing the expression of multiple NF-κB- and c-Jun-driven cytokine genes (45, 48–50), similar to GCs. ERα may displace p65 and CREB and their associated co-regulators from NF-κB binding site (51). Progesterone (P4) is produced at high levels during the menstrual cycle and during pregnancy. P4 signals through the progesterone receptor (PR) and to a lesser extent, through GR and mineralocorticoid receptors. P4 is expressed in different immune cells types, including NK, macrophages, DCs, and T cells (52), and have broad anti-inflammatory effects of the immune system by decreasing leukocytes activation and production of pro-inflammatory mediators (5). NF-κB inhibition is also suggested to play a role in these effects of P4 (53).

Similar to GCs, male steroid hormones demonstrate mostly the suppressive role in immune function (2, 54–57), via binding to androgen receptor (AR), also a member of NR superfamily, and regulation of target gene expression (58). AR recognizes directly the androgen response elements in the regulatory regions of AR target genes (59). Androgens, including dihydrotestosterone and testosterone, generally suppress immune cell activity, by reducing the inflammatory and promoting anti-inflammatory mediators’ expression by macrophages and T cells (5, 60–62). The levels of androgen DHEA are reduced in patients with RA (63) and inflammatory bowel disease (64) suggesting that DHEA may cover many aspects of immune regulatory effects of sex hormones.

Moreover, an indirect immunomodulatory effect of androgens may be related to the anti-inflammatory activity of endogenous GCs due to their effect on the HPA axis (65).

Both GCs and sex steroid modulate the development and function of various cells of innate immunity, including neutrophils, macrophages, natural killer cells, and DC (Table 1). GCs actions include regulation of apoptosis in many cell types: they exert a protective effect in macrophages, by inhibiting activation of caspases and contributing to inflammation resolution (66); however, prolonged usage of GCs promotes apoptosis in macrophages (67), natural killer cells (68), DC (69–71), neutrophils (72, 73), and eosinophils (72). To the contrary, estrogens and androgens increase the number of neutrophils (74, 75).

Glucocorticoids have mainly suppressive effects on the cells of innate immunity (Table 1). High doses of GCs inhibit most of the functions of tissue macrophages, such as chemotaxis, phagocytosis, proliferation, and antigen presentation (67, 76). GCs suppress the expression of various pro-inflammatory cytokines released by macrophages, such as IFN-γ, IL-1α, and IL-1β (76). In addition, the synthesis of anti-inflammatory molecules annexin A1 and GILZ in macrophages contributes to the anti-inflammatory and immunosuppressive action of GCs (28, 29, 77). GCs also inhibit monocytes’ chemotaxis by reducing expression of chemokines, such as CXCL-1, IL-8 and CXCL-2, and CCL2 (78, 79), control granulocyte trafficking by reducing expression of adhesion molecules, such as Mac-1 and L-selectin on neutrophils (80–82), thus limiting the inflammatory response. In addition, GCs prevent neutrophils migration into inflamed tissues via the upregulation of GILZ and annexin A1 (82). Similar to GCs, treatment with estrogens inhibits neutrophils’ activity by restricting their recruitment (83–88) and inhibiting the NFκB-dependent production of major neutrophil chemoattractants CXCL-1, CXCL2, CXCL3, and CXCL8 in experimental models of tissue injury (86–91). Estradiol inhibits neutrophil activation through a reduction in oxidative metabolism (92), adhesion to endothelial cells via upregulation of the anti-inflammatory protein annexin A1 (93), and attenuates the release of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6 in human peripheral blood mononuclear cells (94, 95) and in neutrophils and macrophages (96–99). Interestingly, the inhibition of NFκB activity is a central mechanism underlying these actions (83).

Glucocorticoids and estrogens have both convergent and divergent actions in DCs. GCs inhibit DC function in several ways: by promoting apoptosis (76), disturbing maturation of immature DCs (100), and inducing a tolerogenic phenotype, via downregulating the expression of major histocompatibility complex (MHC)-II and co-stimulatory molecules and cytokines, such as IL-1, IL-6, and IL-12 (101, 102). Such changes are associated with reduced proliferative and T helper 1 (Th1) responses by T cells (103), and increase in immunosuppressive regulatory T (Treg) cells (101). Instead, estrogens promote DC cell differentiation and MHCII expression, and induce the expression of IL-6, IL-23, IL-12, and IL-1β (104–107), thus increasing the type-1 responses (108). On the other hand, similar to GCs, estrogens induce a tolerogenic phenotype in DC, by decreasing the expression of pro-inflammatory cytokines and chemokines, such as IL-6, IFN-γ, IL-12, CXCL8, and CCL2 (109–111), and upregulating inhibitory molecules PD-L1 and PD-L2, and regulatory cytokines IL-10 and TGF-β, thus also leading to a decrease in the Th1 cells activation and a shift toward production of Th2-type cytokines (109, 112).

Controlled elimination of T cells during thymocyte development and T cell-mediated immune responses is essential to prevent immunopathologies, such as autoimmunity and cancer. GCs induce apoptosis in developing thymocytes (113–116) and regulate both “death by neglect” and positive selection (117). The GC-induced apoptosis in thymocytes is also attributed to non-genomic effects of GR (38, 39, 118, 119). Their role in positive selection is inferred from the antagonism between GCs and T cell repertoire (TCR)-activated signals, which allows cells with intermediate TCR affinity to be positively selected (120–122).

The growth suppressive effect of GCs on thymocytes is common to the action of female and male sex hormones. Similar to GCs, estrogens inhibit thymocyte proliferation (123) and induce thymic atrophy (124). Pregnancy is associated with accelerated thymic involution (125, 126). Androgens also restrain active cell cycling and the number of immature thymocytes (127). The number of CD4+ and CD8+ T cells is lower in males around 50–75 of age compared to females, and the diversity of the TCR in females is larger than in males of the same age (128).

Upon TCR activation and stimulation with particular cytokines, naïve mature CD4+ T cells differentiate in the periphery into one of several lineages of T helper (Th) cells that include Th1, Th2, Th17, and Treg cells (129). GCs promote the shift from Th1 to Th2 type immune responses by differentially regulating apoptosis of Th1 and Th2 cells (130), and by interfering with the activity of their master regulators T-bet and GATA-3, respectively (131–133). GCs can also suppress the production of TNF-α, IL-12, and IFN-γ and induce the production of IL-4, IL-10, and IL-13 (13, 130). GCs inhibit the production of Th17-type cytokines in AD (134), although the sensitivity of Th17 cells to GC-induced apoptosis varies dependent on disease-specific microenvironment (135). Treg cells play a critical role in regulating immune responses and peripheral tolerance. GCs upregulate expression of FoxP3, the master regulator of Treg cells, expand Treg cell population (136–140), and increase Treg function in AD (141–143). Expression of GCs’ target gene GILZ also contributes to the GC-mediated regulation of Th1/Th2 balance (144, 145), and the induction of Treg cells by promoting TGF-β-dependent FoxP3 expression (136).

Sex steroids also modulate the differentiation and function of all subsets of T cells (75, 146–148). Contrary to GCs, estrogens promote INF-γ production by Th1 cells in both human and mice (149–151), via potentially direct interaction of ER with the Ifng promoter (150, 152), upregulation of Th-1 transcription factor T-bet (151, 153), or via microRNA-dependent suppression of IFN-γ expression (154). However, high levels of estrogen skew the immune response from Th1 to Th2-type (155–157), similar to GCs. Estradiol also regulates anti-inflammatory Th2 shift by activating SGK1 kinase (158). The effects of estrogens on Th17 subset are different depending on experimental model, leading to enhancement (159, 160) or decrease (161) of Th17-dependent inflammation. Like GCs, estrogens promote the expansion of Treg cells (162, 163) by upregulating the expression of FoxP3, PD-1, and CTLA-4 (162–166), therefore, GCs and estrogens may co-operate in promoting the Treg development and activity.

Glucocorticoids and estrogens elicit opposite effects on B cells. GCs have a pro-apoptotic effect on developing B lymphocytes in the bone marrow (167, 168). On the other hand, B-lymphoblastic leukemia cells are resistant to GC-induced apoptosis, due to enhanced expression of B-cell lymphoma-2 protein (167, 169). GILZ mediates GC-induced apoptosis in B cells as shown by the accumulation of B cells in the bone marrow and in the periphery in GILZ-deficient mice, due to reduced B cell apoptosis (170). GCs affect directly humoral response by reducing circulating immunoglobulins (Igs) although some studies have shown an increase of IgE production in conjunction with IL-4 (171–173). Instead, enhanced antibody production is observed in women, suggesting that female sex hormones stimulate B cell-mediated responses. Estrogen treatment also interferes with normal tolerance of naive DNA-reactive B cells, thus contributing to the development of AD. Elevated estrogen alters the negative selection of DNA-reactive B cells in the periphery (174, 175), interfering with proper B cell receptor signaling and regulation of B cells activation and apoptosis (176, 177). Thus, pharmacologic treatment with synthetic GCs may be useful in suppression of the enhanced B cell activities in AD.

Innate lymphoid cell is a most recently identified immune cell type, which contributes to inflammation, immunity, and the maintenance of tissue integrity and homeostasis (178). Recent evidence demonstrated that group 2 ILC2s are present in the uterus under control of estrogens and are increased upon estrogen administration (179). It is, therefore, possible that estrogens modulate tolerance via ILC2-mediated modulation of the protective Th2 shift in pregnancy. Instead, ILC2 promote lung inflammation during asthma (180). Interestingly, male mice have reduced numbers of ILC2s in peripheral tissues compared to females, and the number of ILC2s in the lungs is negatively regulated by androgens (181), consistent with the overall suppressive role of male steroids in immunity. GCs were shown to modulate the cytokine production by the ILC2s, thus these finding suggests a modulatory role of steroid hormones in ILCs and homeostasis of specific tissues.