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The role of glucocorticoids and progestins in inflammatory, autoimmune, and infectious disease A. Sasha Tait, Cherie L. Butts, and Esther M. Sternberg1 Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Rockville, Maryland, USA

Abstract: A bidirectional communication exists between the CNS and the immune system. The autonomic nervous system, through neurotransmitters and neuropeptides, works in parallel with the hypothalamic-pituitary-adrenal axis through the actions of glucocorticoids to modulate inflammatory events. The immune system, through the action of cytokines and other factors, in turn, activates the CNS to orchestrate negative-feedback mechanisms that keep the immune response in check. Disruption of these interactions has been associated with a number of syndromes including inflammatory, autoimmune, and cardiovascular diseases, metabolic and psychiatric disorders, and the development of shock. The hypothalamic-pituitary-gonadal axis also plays an important part in regulating immunity through the secretion of sex hormones. Although numerous studies have established a role for immunomodulation by estrogen and testosterone, the role of progesterone is less well understood. Progesterone is crucial for reproductive organ development and maintenance of pregnancy, and more recent studies have clearly shown its role as an important immune regulator. The main focus of this review will be about the role of steroid hormones, specifically glucocorticoids and progesterone, in inflammatory responses and infectious diseases and how dysregulation of their actions may contribute to development of autoimmune and inflammatory disease. J. Leukoc. Biol. 84: 924 –931; 2008. Key Words: progesterone 䡠 polymorphism 䡠 inflammation

INTRODUCTION The body’s response to stress involves activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous systems (ANS) to coordinate behavioral, metabolic, and immune changes, thus restoring homeostasis (Fig. 1) [1, 2]. Acute activation of the stress systems primes the body physically and mentally for a “fight-or-flight” response as well as for potential injury. These events are mediated initially by the signaling molecules of the HPA axis and sympathetic ANS, the glucocorticoids, and catecholamines, respectively. If injury or infection occurs, the immune system will release cytokines into 924

Journal of Leukocyte Biology Volume 84, October 2008

the circulation, which in turn can signal the brain, further activating the HPA axis and ANS [3, 4]. This cytokine-driven response provides a negative-feedback loop, suppressing the inflammatory event, restoring homeostasis, and preventing the development of dysregulated immune responses, thus potentially triggering autoimmune disease. Recurrent or chronic activation of the acute stress response can create an environment in which the immune response is continuously suppressed, thereby increasing susceptibility to infectious agents [5, 6]. Chronic stress responses can also have the opposite effect on the immune system, leading to an increase in inflammatory responses and development of autoimmune disease [6]. This is thought to be mediated primarily by an impairment of glucocorticoid action that results in dysregulation of the immune response. Impairment can occur at the level of the organs of the HPA axis (brain, pituitary, and adrenals) or at the level of the glucocorticoid receptor (GR), which mediates glucocorticoid action. Immune responses may also be regulated by other steroid hormones, including progesterone. Autoimmune/inflammatory disease is expressed in a disproportionately higher incidence in females compared with males [7–9], indicating a role for the sex hormones in disease susceptibility or progression. In addition, autoimmune disease manifestation is altered during pregnancy, in which elevated levels of sex hormones, including progesterone, are produced. TH1-related diseases, such as rheumatoid arthritis (RA) and multiple sclerosis (MS), tend to improve [10, 11], whereas TH2-related disease, such as systemic lupus erythematosus (SLE), tend to worsen during pregnancy. This provides further support for a role for sex hormones in regulation of immune responses and immune-related diseases. More recently, the role of progesterone in regulation of the immune response during the nonpregnant state has also been examined. Glucocorticoids and progesterone are steroid hormones that can diffuse easily across the plasma membrane. Once in the cytosol, they can bind to their respective cytoplasmic receptors. Ligand-bound receptors can dimerize and translocate to the nucleus of the cell to act as transcription factors to promote or prevent transcription of target genes. Alternatively, these

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Correspondence: Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health/NIH, 5625 Fishers Lane (MSC-9401), Rockville, MD 20852, USA. E-mail: sternbee@mail.nih.gov Received February 12, 2008; revised May 15, 2008; accepted June 5, 2008. doi: 10.1189/jlb.0208104

0741-5400/08/0084-924 © Society for Leukocyte Biology

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Fig. 1. Schematic outlining the bidirectional communication between the hypothalamic-pituitary axes, the ANS, and the immune system (reproduced from ref. [122]). Hormones released by the adrenals and gonads, such as glucocorticoids and progesterone, respectively, work in parallel with neurotransmitters and neuropeptides to regulate the immune system. In turn, cytokine signaling provides stimulus or feedback to the hypothalamus to regulate the hormonal and neuronal response. Dotted lines represent negative regulatory pathways, and solid lines represent positive regulatory pathways. A1, C1, A2, C2, Brainstem adrenergic nuclei; ACTH, adrenocorticotrophin hormone; AVP, arginine vasopressin; CRH, corticotrophin-releasing hormone; DHEA, dehydroepiandrosterone; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LC, locus ceruleus; LH, luteinizing hormone; PNS, peripheral nervous system; SNS, sympathetic nervous system; T3, tri-iodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; Vagus n., vagus nerve

ligand-bound receptors can bind as single polypeptides to other transcription factors, interfering with their actions to promote changes in cellular activity. Although certain cells are associated with primary production of specific steroid hormones, all steroid hormones are formed from a common precursor (cholesterol), and any cell with the appropriate enzymes can potentially produce specific steroid hormones. This review will focus on the roles of glucocorticoids and progesterone in regulation of immunity and will address the role of steroid hormone resistance or hypersensitivity in susceptibility and development of autoimmune/inflammatory disease.

GLUCOCORTICOIDS Glucocorticoids are a class of steroid hormones secreted by the adrenal cortex following activation of the HPA axis by inflammatory and stress-related stimuli [1, 2, 12]. As a result of their therapeutic use, these hormones are considered powerful immunosuppressants at pharmacological doses, yet at physiological concentrations, glucocorticoids are immune-modulating. They affect all aspects of immune cell function (for more detailed review, see ref. [13]), such as antigen presentation [14 –16], lymphocyte proliferation and trafficking [17–19], and also shifting the cytokine response from a TH1 to TH2 pattern to suppress inflammation [20, 21].

Glucocorticoid action is mediated through cytosolic receptors, GRs that belong to the nuclear hormone receptor superfamily [22]. GRs are ligand-induced transcription factors that can regulate gene expression by direct interaction with specific promoter sequences, called glucocorticoid response elements. They can also control gene expression through protein–protein interactions with other transcription factors such as NF-␬B, AP1, STAT, and NFAT [23–25]. The anti-inflammatory effects of glucocorticoids are mediated through negative interaction with NF-␬B and AP1, which are well-characterized inducers of proinflammatory cytokine expression. There are multiple isoforms of GR arising from alternative splicing and translational events of a single gene (NR3C1) located in chromosome 5q31-32 [22, 26]. The GR␣-A isoform is the full-length receptor consisting of 777 aa, which bind ligand and mediate glucocorticoid action. Two truncated isoforms, GR␤ (742 aa) and GR-P (676 aa), are unable to bind ligand and have been shown to mediate GR␣ activity. The role GR␤ actually plays is controversial, as it has been shown to have a dominant-negative effect on GR␣ activity [27, 28] as well as a synergistic effect [29]. Although normally expressed at low levels compared with GR␣ [28], GR␤ expression can be increased in tissue during disease. This high expression has been associated with decreased sensitivity to glucocorticoids [27, 30]. It is possible that changes in GR␤ expression may be one of the feedback mechanisms used by cells to regulate

Tait et al. Glucocorticoids and progesterone in disease susceptibility

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normal GR activity, and aberrant expression coincides with the development or severity of disease. Basal expression of GR protein is distinct in different tissues and cell types of the immune system that reflect their unique sensitivity to glucocorticoids. At the tissue level, the thymus and lymph nodes express high levels of GR and are sensitive to glucocorticoids, whereas the spleen expresses much lower levels [31]. Concordantly, immature thymocytes found primarily in the thymus express high levels of GR [32], whereas splenic T cells express low levels [31]. Cell types that show minimal expression of GR␣-A and show minimal effects by glucocorticoids include neutrophils [31, 33]. The other isoforms of GR, GR␤ and GR-P, show distinct subcellular and tissue expression patterns as well [26] and in turn, regulate the function of the full-length receptor. This is seen in neutrophils, where GR␤ expression is much greater than GR␣ expression [33]. A possible membrane-associated, glucocorticoid-responsive receptor has been reported in neutrophils and B lymphocytes [34, 35]; however, the actual protein has not yet been identified.

PROGESTERONE Progesterone is a steroid hormone primarily secreted by the granulosa cells and the corpus luteum in the ovary. During pregnancy, a major source of progesterone also comes from the placenta. Males also produce progesterone in the adrenal gland and testes, as this is a precursor of testosterone. In females, this hormone plays a crucial role in mammary gland development [36], ovulation [37], embryo implantation, and maintenance of pregnancy [38]. Progesterone effects on immunity have also been reported and most notably studied in the context of pregnancy, in which elevated levels of steroid hormones, including progesterone, are produced. There is a possibility of fetal antigens stimulating the maternal immune system, thereby requiring localized immune suppression to prevent the loss of the fetus [39]. Pregnancy is associated with inhibition of TH1 signaling by peripheral T lymphocytes [40, 41], and progesterone has been shown to inhibit T cell, macrophage, and NK cell activity [42]. Progesterone has also been shown to decrease production of NO and nitrite by macrophages [43]. Progesterone is also secreted during the nonpregnant state and has been shown to have direct effects on immune cells. Administration of progesterone into the female reproductive tract results in increased numbers of Langerhans cells, a population of dendritic cells (DCs) found in the skin [44]. However, the exact function of these cells was not examined in this study. We have shown direct effects of progesterone on DC function, especially mature DCs. These results include inhibition of proinflammatory cytokine secretion, down-regulation of DC-associated activation markers (MHC class II, CD80), and reduced T cell-proliferative capacity by these cells [45]. A similar effect on DC function was reported using human chorionic gonadotropin, which induces progesterone secretion in the placenta [46]. The action of progesterone is mediated through cytosolic progesterone receptors (PRs) and possibly also by putative membrane-associated PRs (mPRs) [47]. PRs, like GRs, belong 926


to the nuclear hormone receptor superfamily of transcription factors, where ligand binding induces changes in gene expression through direct binding to promoter elements [48] or through protein–protein interactions with other transcription factors [49]. There are three isoforms of PRs (PR-A, PR-B, and PR-C) arising from the NR3C3 gene located at 11q22-23, and the full-length PR-B encodes 933 aa [50 –54], as the main, functional form. The different isoforms have specific tissue expression patterns that can be modified following exposure to hormones [55–57]. Mice lacking the two predominant isoforms, PR-A and PR-B, display a variety of reproductive abnormalities, uterine inflammation, and impaired thymic function [38]. There have been several reports of mPRs in epithelial and sperm cells, and one recent report in T-lymphocytes [58 – 61]. These are thought to be G-coupled protein receptors that rapidly transduce hormone-induced signals across the cell membrane in cells that do not express cytosolic PRs. Three receptor proteins have been identified, each encoded by a unique gene. However, there is some controversy as to whether these membrane proteins truly mediate progesterone effects [46, 62]. In nonpregnant animals, PR has been identified in a variety of immune cell types such as immature DCs [45], activated peripheral blood lymphocytes of females [63], and inflammatory cells from synovial tissue in RA patients [64]. No expression of PR has yet been reported at the protein level in resting lymphocytes, macrophages, or NK cells. Reports suggest that these particular cell types exhibit anti-inflammatory responses to progesterone, because of the presence of mPRs [61] or the presence and activity of a progesterone-induced blocking factor. This 34-kDa protein has been identified in immune cell types that lack PR and to mediate progesterone-induced, antiinflammatory actions and plays a crucial role in progesterone regulation of the immune response during pregnancy [65, 66].

FACTORS INFLUENCING RECEPTOR ACTIVITY AND DISEASE SUSCEPTIBILITY AND PROGRESSION The classical immune-regulatory role of steroid hormone action is mediated through the cytoplasmic receptors. Hormone-induced GR and PR activity has been shown to bind to components of NF-␬B and AP-1, leading to decreased expression of proinflammatory cytokines such as TNF-␣ and IL-1␤ [21, 45] and increased expression of TH2 cytokines such as IL-4 and IL-10 [21, 67]. Modifications to receptor function can lead to changes in hormone sensitivity, leading to loss of homeostasis and increased incidence of disease. Factors that can influence receptor function include changes in receptor expression, such as increased expression of nonfunctional isoforms and presence of mutations or polymorphisms.

GR isoforms Changes in GR isoform expression have been found in patients with inflammatory diseases. In particular, increased expression of GR␤, which is associated with changes in GR activity, has been reported in PBMCs from patients with inflammatory liver http://www.jleukbio.org

TABLE 1. SNP #

Position

Polymorphisms Identified in Human NR3Cl Associated with Phenotypic Changes Cohort

rs10052957

5⬘UTR

Healthy male

rs6189/ rs6190

E22E/R23K

Elderly male (⬎73 years old) Elderly (53–82 years old) MS

rs6195

N363S

Healthy male Healthy Coronary artery disease Obesity female Obesity male Obesity

rs41423247

Intron 2

Healthy

Healthy male

rs6198

9␤ 3⬘UTR

Healthy (⬃50 years old) Elderly (53–82 years old) RA Elderly (53–82 years old) Healthy male

Phenotype

n

carriers of the mutant allele—higher evening cortisol levels heterozygous subjects—lower levels of Creactive protein and higher survival rate in 4-year follow-up study heterozygous subjects—GC resistance, lower LDL cholesterol and insulin levels heterozygous subjects—more aggressive disease phenotype mutant allele carriers—increased salivary cortisol response to psychosocial stress associated with GC resistance heterozygous subjects—increased BMI, increased cortisol sensitivity, and increased GC-induced insulin response carriers of mutant allele—increased frequency of disease heterozygous subjects—increased BMI and food intake heterozygous subjects—increased waist-to-hip ratios carriers of the mutant allele—high BMI

129

homozygous subjects—more sensitive to topical budesonide and less sensitive to dexamethasone-induced WBC lysozyme release homozygous subjects—attenuated salivary cortisol response to psychosocial stress and ACTH homozygous subjects—slightly increased BMI and serum leptin levels carriers of mutant allele—increased sensitivity to GC with allele dosage carriers of the mutant allele—increased frequency of disease homozygous subjects—decreased colonization of Staphylococcus aureus in nasal passage heterozygous subjects—high GC-induced ACTH levels

Population

Ref.

Swedish

[78]

21

Dutch

[79]

18

Dutch

[80]

24

Dutch

[81]

10

German

[82]

Dutch

[83]

Australian Caucasian Italian

[84]

English

[86]

Australian Caucasian Scottish

[87]

18

German

[82]

36

Swedish

[89]

Dutch

[90]

11

English

[91]

65

Dutch

[92]

27

German

[93]

8 107 13 7 81 6

310

[85]

[88]

BMI, Body mass index; GC, glucocorticoid; LDL, low-density lipoprotein; WBC, white blood cell; UTR, untranslated region.

disease [68], autoimmune hepatitis [69], RA [70], and glucocorticoid-resistant ulcerative colitis [71, 72]. Increased GR␤ has also been shown in immunoreactive cells in severe asthma [73] and bronchoalveolar lavage macrophages in glucocorticoid-insensitive asthma [74]. There is much debate as to what triggers the increased expression of this isoform. Recent evidence suggests that exposure of airway smooth muscle cells to proinflammatory cytokines such as TNF-␣ and IFN-␥ can amplify GR␤ expression [28, 75], indicating the inflammatory event triggers the change in GR isoform expression and thus, glucocorticoid sensitivity.

GR polymorphisms One of many factors that could modify receptor activity leading to the development of disease is the genetic background of the individual. To date, there have been ⬃550 single nucleotide polymorphisms (SNPs) identified in the human GR gene (NR3C1). Since it was first cloned in 1985 [76], many genetic

changes have been identified in individuals with glucocorticoid-resistant metabolic disorders [77]. More recently, larger cohort studies have been performed showing association between genetic changes in GR with phenotypic changes (Table 1). The role of these polymorphisms in inflammatory and autoimmune diseases has not been investigated thoroughly; however, interesting associations have been reported in RA and SLE [91, 94, 95]. One prominent polymorphism associating GR with immune regulation is the rs6198 polymorphism (A/G), located in the 3⬘ UTR of the GR␤ transcript. This polymorphism was first reported to occur in patients with RA, in which there was a slightly greater incidence of the mutant G allele in a small cohort from England (n⫽30) [91]. A subsequent, larger study (n⫽198) about RA in a similar population group (English) did not see any linkage of the polymorphism with the disease [96]. Interestingly, a multiracial study reported similar frequencies of wild-type and mutant allele expression in asthmatic and control subjects in U.S. Caucasian,


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African American, and Hispanic groups, yet there was a higher incidence of the mutant allele in Dutch Caucasian asthmatics [97]. Functional in vitro studies of this polymorphism have shown that the mutation increases stability of GR␤ mRNA and protein [91, 98]. As stated previously, the ␤ isoform is thought to have a dominant-negative effect on GR␣; therefore, increased expression could induce glucocorticoid resistance. A subsequent, ex vivo study about PBMCs showed that homozygous carriers of the SNP exhibited less glucocorticoid-induced repression on IL-2 expression [99]. This indicates that homozygous carriers of the mutant allele are less able to suppress proinflammatory signaling. Another study of homozygous carriers (n⫽65) showed reduced colonization of S. aureus in nasal passages in an elderly (⬃70 years old) Dutch population [92]. These data indicate that the immune system in homozygous carriers is able to clear infections, but perhaps once triggered, there is a delay in switching off the proinflammatory response. The fact that these elderly Dutch subjects do not have RA is consistent with the multigenic/polygenic nature of the disease, which also requires environmental exposure(s) to trigger disease expression. Nonetheless, the data indicate that homozygous carriers of the mutation may be more susceptible to inflammation as a result of glucocorticoid resistance and resultant, reduced immune suppression. One failure of many of the genetic studies is that the majority of mutations identified in patients has been heterozygous, where the wild-type and mutant allele are present at the DNA level. Subsequent in vitro studies using homozygous mutants have clearly demonstrated that genetic changes affect the function of the receptor. However, to date, there has been no confirmation that patients express the mutant receptor. Considering there is expression of different receptor isoforms, and these isoforms can have tissue-specific expression patterns, further studies need to be performed to clarify whether identified mutations are related directly to a disease state. Another crucial factor for these types of genetic studies is to obtain appropriate population controls to determine the true etiology and functional significance of polymorphism-disease association.

PR protein expression There are differences between males and females in the incidence of autoimmune disorders [7–9] and infections [100 – 102]. Females have been shown to be immunologically more reactive than males with higher antibody-mediated responses [103], higher expression levels of the proinflammatory cytokine TNF-␣ [104], and increased ability to combat infections. Previous studies have focused on the contributing role of estrogen in the development of disease [105]. More recently, progesterone effects on disease have also proven to be important to consider. A recent report showed that reduced activation of PR by estrogen can occur during SLE [106]. Whether estrogen effects on PR occur in other inflammatory disease states and whether this occurs at the level of changes in PR isoform expression have not yet been examined.

PR polymorphisms More than 670 SNPs have been identified in the human PR gene, many of which have been associated with increased risk of developing ovarian, endometrial, and breast cancer [107– 928


109]. PR SNPs have also been associated with preterm labor and delivery [110], recurrent abortions [111], and migraineassociated vertigo in females [112]. With the predominance of PR mutations in cancer, it will be important to determine whether certain SNPs in PR related to cancer risk are a result of effects on immune cells and the inability of the host to mount a potent anti-tumor immune response [6].

Infectious disease and hormone function Host factors can contribute to infectious disease susceptibility and progression, as evidenced, for example, by gender disparities in parasitic and bacterial infections [100 –102]. At the cellular level, studies have shown that treatment with the gram-negative bacterial endotoxin LPS modifies GR and PR expression in macrophage and bronchial epithelial cells [113, 114], which could lead to inappropriately timed hormone responses. For instance, PR expression has been shown to decrease, leading to hormone resistance, and GR is up-regulated early (within 4 –16 h), which could induce suppression of the immune response. We have shown that toxins produced by gram-positive bacteria, such as lethal toxin from Bacillus anthracis, lethal toxin from Clostridium sordellii, and Toxin A and B from Clostridium difficile, attenuate glucocorticoid and progesterone effects [115–117]. Furthermore, we showed that C. sordellii lethal toxin had a more pronounced effect on glucocorticoid suppression of proinflammatory signaling in female Fischer rats in the diestrus phase, where progesterone levels were high [117]. Considering that clostridial infections and clostridial toxic shock have been reported to occur increasingly in pregnant women [118 –120], it is possible that changes in GR and PR expression and activity as a result of pregnancy, the infectious agent, or other host factors could contribute to disease susceptibility and progression. Why these receptors are targeted and how changes in their activity are linked to the disease state are not fully understood, but it is known that disruption of the HPA axis can lead to increased mortality in mice treated with B. anthracis lethal toxin [121].

CONCLUSION Glucocorticoids play a crucial role in regulating the immune response, from initial activation to eventual suppression and restoration of homeostasis. Emerging evidence indicates that progesterone also plays an important role outside of the context of pregnancy. When the actions of these hormones are impaired at the level of their receptors through changes in isoform expression or genetic mutations, the resulting dysregulation of the immune response may enhance susceptibility to development of infectious or inflammatory disease. As a result of the complexity of neuroendocrine-immune interactions, no single event that changes GR and PR activity is likely to be responsible for the development of disease, but these host factors together can contribute to disease progression.

ACKNOWLEDGMENT We thank Dr. Marni Silverman for assisting with the preparation of the manuscript. http://www.jleukbio.org

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