One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids

Abstract

Glucocorticoids are essential steroid hormones secreted from the adrenal gland in response to stress. Since their discovery in the 1940s, glucocorticoids have been widely prescribed to treat inflammatory disorders and hematological cancers. In the traditional view, glucocorticoids are regarded as anti-inflammatory molecules; however, emerging evidence suggests that glucocorticoid actions are more complex than previously anticipated. The anti-inflammatory activity of glucocorticoids is attributed to the repression of pro-inflammatory genes through signal transduction by their steroid receptor, the glucocorticoid receptor (GR). The mechanisms modulating the pro-inflammatory effects of glucocorticoids are not well understood. In this review, we discuss recent findings that provide insights into the mechanism by which GR signaling can play a dual role in the regulation of the immune response. We hypothesize that these apparently opposite processes are working together to prepare the immune system to respond to a stressor (pro-inflammatory effects) and subsequently restore homeostasis (anti-inflammatory effects). Finally, we propose that determining the mechanisms which underlie the tissue-specific effects of glucocorticoids will provide an excellent tool to develop more efficient and selective glucocorticoid therapies.

Figure 1. Regulation of glucocorticoid secretion in response to stress by the hypothalamic-pituitary-adrenal (HPA) axis

Upon exposure to environmental or psychological stress the hypothalamus is stimulated to release corticotropin-releasing hormone (CRH). CRH then stimulate the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH). In turn, ACTH targets the cortex of the adrenal glands to release cortisol into the blood stream. Once in circulation, cortisol can be converted to the inactive form, cortisone, by type 2 11β-hydroxysteroid dehydrogenase. Conversely, type 1 11β-hydroxysteroid dehydrogenase converts cortisone to cortisol. Glucocorticoids exert their effects by binding to their receptor, the glucocorticoid receptor (GR). GR is expressed in virtually all cell types and tissues. Thus, GR signaling plays an important role in the modulation of a large number of biological functions in immune cells and in several organs and tissues, including brain, liver, heart, lungs, adipose tissue, reproductive system, stomach and muscle.

Figure 2. Schematic representation of the GR structure and signaling Pathways

(A) This panel shows the GR domains and regions involved in transactivation (AF1 and AF2), dimerization, nuclear localization, and hsp90 binding. NTD, N-terminal domain; DBD, DNA-binding domain; H, hinge region; LBD, C-terminal ligand domain. (B) GR can signal in a non-genomic manner by modulating the activity of several kinases, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and AKT. GR regulates gene expression by three mechanisms: 1) Direct, activated GR binds to GREs or nGREs on the promoter or sequence of target genes; 2) Tethering: GR tethers itself to other DNA-bound transcription factors; 3) Composite: GR binds directly to a GRE and interacts with neighboring DNA-bound transcription factors. BTM, Basal transcription machinery; NFκB, Nuclear factor-κB; STAT, Signal transducer and activator of transcription; AP-1, Activator protein-1.

Figure 3. Anti-inflammatory effects of glucocorticoids

Exposure to pathogens leads to a fast activation of the immune response. Glucocorticoids modulate the inflammatory response by repressing the expression of pro-inflammatory cytokines by immune cells. In addition, glucocorticoids can repress the expression of adhesion molecules, which prevents rolling, adhesion and extravasation of neutrophils to the site of inflammation. Glucocorticoids also induce the expression of annexin-1. Synthesis of annexin-1 promotes neutrophil detachment and apoptosis. Chronic exposure to glucocorticoids induces a switch in resident macrophages gene expression profile from pro-inflammatory to anti-inflammatory, and increases macrophages phagocytic activity. Finally, glucocorticoids act on T cells by blocking T helper (Th1) and Th2-derived cytokine production and inducing cell death.

Figure 4. Glucocorticoids exert anti-inflammatory effects by repressing the expression of AP-1 and NFκB

Exposure to pathogens triggers a signaling cascade that leads to the activation of pro-inflammatory transcription factors, including AP-1 and NFκB. Activation of GR results in its translocation to the nucleus. Once in the nucleus GR represses AP-1 and NFκB. GR can repress AP-1 by the following mechanisms: (i) In some promoters, GR binds to a GRE and simultaneously interacts with c-Jun to repress AP-1 activity; (ii) GR can also physically interact (tethering) with c-Jun, which represses AP-1 activity and the transcription of inflammatory genes. NFκB activity can be repressed by GR through the following mechanisms: (i) GR can physically interact with p65, which represses the activity of NFκB; (ii) GR can recruit GRIP (GR interacting protein) which blocks the formation of the NFκB/IRF3 (interferon regulatory factor 3) heterodimer; (iii) GR can prevent the phosphorylation and activation of RNA polymerase II (Pol II) by blocking the recruitment of pTEFb (positive transcription elongation factor); (iv) GR is also able to repress NFκB by recruiting HDAC (histone deacetylases); (v) GR prevents NFκB from interaction with p300 and CPB (CREB1-binding protein); (vi) GR can interact with p53, which alters NFκB pro-inflammatory transcriptional activity.

Figure 5. Glucocorticoid-mediated modulation of pro-inflammatory pathways

(A) GR can drive the expression of Toll-like receptor 2 (TLR2) by interacting with STAT5 and NFκB. TLR2 recognizes bacterial cell wall component peptidoglycan. Upon stimulation, MYD88 binds to the cytoplasmic portion of TLR2. This event leads to recruitment and activation of IRAK1, IRAK4, TRAF6, ultimately leading to the downstream signaling activation of pro-inflammatory transcription factors which drives the expression of inflammatory cytokines, including IL-6 and IL-8. (B and C) Glucocorticoids regulate the expression of NLRP3 and P2Y₂R by mechanisms that are not well understood. NLRP3 regulate the immune system response to injury or pathogens by sensitizing macrophages to extracellular ATP (danger signal) and inducing the synthesis of IL-1β. P2Y₂R is a G protein-coupled receptor that is activated in response to ATP, which stimulates the activation of PLC (Phospholipase C) and PKC (protein kinase C), and the subsequent downstream signaling. Glucocorticoids can up-regulate the expression of P2Y₂R by enhancing the ATP-dependent activation of p38, which leads to the expression of the pro-inflammatory cytokine IL-6.