Cortisol and the Immune Response

Cortisol is a steroid hormone, classified as a member of the glucocorticoid family of hormones. Cortisol is involved in a plethora of physiological processes in order to maintain homeostatic conditions in the body (McEwan et al, 2007). Cortisol is produced by the adrenal gland in response to stress and reduced levels of blood-sugar (Kamba et al, 2016); however, importantly cortisol is also released in a circadian fashion under homeostatic conditions (Krieger et al, 1971).

Cortisol is immunosuppressive in function, and elicits its immunosuppressive effects by downregulating key inflammatory transcription factors, NF-kB and AP-1, and upregulating the suppressor of cytokines (SOCS), which in turn inhibits STAT phosphorylation and downstream pro-inflammatory gene transcription, essentially weakening the pro-inflammatory response (Heck et al, 1997; Jonat et al, 1990). Therapeutic strategies exploiting these immunosuppressive functions have long existed, and synthetic glucocorticoids are widely prescribed to treat inflammatory and autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis and multiple sclerosis, and importantly are used to reduce immune-mediated rejection of transplanted tissue (Busillo et al, 2013; Steiner and Awdishu et al, 2011; Da Silva et al, 2006; Reichardt et al, 2006; Shimada et al, 1997). However, dysregulated cortisol levels are associated with pathogeneses and tumourigenesis (Cohen et al, 2012; Moreno-Smith et al, 2010).

Cortisol is a product of neuroendocrine signalling, which is initiated by the release of corticotropin-releasing factor (CRH) from the hypothalamus. Binding of CRH to the CRH receptor located on the anterior pituitary gland leads to the secretion of adrenocorticotropic hormone (ACTH), which subsequently targets the adrenal glands, stimulating cortisol release (Hodges and Sadow, 1969). Cortisol is secreted into the blood and transported in the circulatory system bound to corticosteroid-binding globulin (CBG), which facilitates the transport and cellular diffusion of cortisol (Seckl et al, 2004). Negative regulation of cortisol occurs via a negative feedback loop mediated by the expression of adrenocorticosteroid receptors which modulate corticotropin release from the pituitary (Sapolsky et al, 1983). Cortisol secretion can be positively regulated by stress signals, macrophage-secreted IL-1 and T cell-secretion of glucocorticoid response modifying factor (GRMF) (Fairchild et al, 1994).

Once transported inside the cell, cortisol binds to the glucocorticoid receptor (GR or GCR), also known as NR3C1. GCR is an intracellular protein which is expressed by almost cell types and regulates a variety of processes such as immune response, metabolism and development (Hollenberg et al, 1985). The GCR consists of three domains; an N-terminal transactivation domain (NTD), a DNA-binding domain (DBD), and a C-terminal domain essential for ligand binding (LBD) (Kumar et al, 2005). Expression analysis studies of the GCR found two splice variants, with the activate isoform GCRa most highly expressed in the CNS and macrophages, with relatively high expression reported in the heart, lungs and kidney compared with colonic tissue (Pujols et al, 2002). Interestingly, GCRa expression was found not be affected by chronic stress, however a study has shown that chronic stress led to increased expression GCRb and reduced expression of heterodimeric GCRa/b, suggesting a point of negative regulation as GCRb can suppress GCRa activity (Miller et al, 2008; Derijk et al, 2001). The bioavailability of cortisol is regulated by the conversion of cortisone to cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β- HSD1), with 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) oxidizing and converting cortisol back into its inactive form (Yang et al, 2008).

In the absence of cortisol, the GCR is retained in the cytosol in a complex containing chaperone proteins heat shock proteins (hsp) 70 and 90 and p23 (Grad and Picard, 2007). Cortisol binds intracellularly to the glucocorticoid-response elements (GRE) located on the DNA-binding domain of the GCR. The GRE induces a conformational change in the GCR which subsequently regulates the activity of RNA polymerase II, inducing the transcription of a wide range of genes (Rosnefeld et al, 2001; Beato et al, 1994). The GCR can also bind directly to several other transcription factors leading to their activation, for examples NF-kB, STAT1 and AP-1.

Much evidence exists for the signalling of GCR in the absence of genomic stimulation, adding further complexity to GCR signal transduction. Multiple accessory proteins were demonstrated to activate downstream pathways such as MAPK, AKT and PI3K in a genomic-independent manner (Groeneweg et al, 2011; Samarasinghe et al, 2012).

Reduced levels of cortisol contribute to a lack of immune regulation, thereby allowing the chronic pro-inflammatory response to ensue in the absence of glucocorticoid regulation, leading to multiple pathogenic states (Nathan, 2002). A recent study identified that cortisol inhibits NF-kB and MAPK activation, specifically by inhibiting the phosphorylation of both IkBa, the inhibitory subunit of NF-kB, and phosphorylation of MAPK (Dong et al, 2018). Additionally, it has been demonstrated that cortisol upregulates the expression of SOCS1 and SOCS2, inhibiting JAK/STAT signalling and reducing downstream signal transduction (Philip et al, 2012). However, elevated levels of cortisol prior to pathogenic insult were found to induce a robust pro-inflammatory response, suggesting dysregulated levels promote inflammatory pathogenesis (Frank et al, 2010; Sorrells et al, 2009). Consistent with the role of cortisol in enhancing the immune response, glucocorticoids were recently demonstrated to upregulate crucial signalling molecules of the NLRP3inflammasome and in this way, sensitizing cells to the ATP – induced pro-inflammatory response (Busillo et al, 2011).

Chronic stress is widely accepted as a risk factor for disease (Cohen et al, 2007). It has been demonstrated in multiple studies that chronic stress leads to upregulation of GCR (Cole, 2008; Miller et al, 2002; Stark et al, 2001). Notably, stress is associated with cancer risk via the disruption of the circadian rhythm, and there is evidence for increased incidence of breast and colorectal cancer in night-shift workers (Schernhammer et al, 2003; Sephton et al, 2000). Additionally, cortisol was shown to increase VEGF-induced angiogenesis, which promotes tumour metastasis (Lutgendorf et al, 2003). Moreover, mutations in the GCR gene are associated with rheumatoid arthritis (Donn et al, 2007).

Glucocorticoids have been used for the treatment of haematopoietic malignant cancers for many years, with the development of the synthetic glucocorticoid, dexamethasone. Dexamethasone is routinely used in the clinic in combination with chemotherapy to promote apoptosis for the treatment of multiple cancers, including multiple myeloma, acute lymphoblastic leukaemia (ALL), and lymphomas (Kufe et al, 2003). However, the role of glucocorticoids in inducing or inhibiting tumourigenesis remains controversial, and is at least in part cancer-type specific. Overall, dysregulated cortisol levels and signalling leads to pathogenesis and tumourigenesis and must be regulated to retain the homeostatic functions without eliciting detrimental effects on the immune response.