By Sinéad Kinsella PhD
Cortisol is a steroid hormone, classified as a member of the glucocorticoid family of hormones which 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).
The Hypothalamic-Pituitary-Adrenal (HPA) axis
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).
Cortisol and the Glucocorticoid Receptor
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).
Canonical GCR signalling
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.
Non-canonical GCR signalling
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).
Cortisol and the inflammatory response
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).
Stress, cortisol and disease
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).
Cortisol in cancer therapy
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.
Figure 1: Regulation of Cortisol secretion by the Hypothalamus-Pituitary Axis (HPA). The hypothalamus is stimulated by neurotransmitters to produce and secrete corticotropin- releasing hormone which binds to receptors on the anterior pituitary, inducing the secretion of adrenocorticotropic hormone. Subsequent signalling to the adrenal cortex leads to the production and secretion of cortisol into the blood stream where it is transported to multiple organs. Cortisol can inhibit the immune response via transcription factors NF-kB or AP-1, and upregulate apoptosis, although its’ role in disease is diverse. Elevated levels of cortisol and the cortisol receptor (glucocorticoid receptor, GCR) have been shown to induce inflammation.
- Beato M. Gene regulation by steroid hormones. Cell. 1989. 56(3):335–44.
- Busillo JM, Cidlowski JA. The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore. Trends Endocrinol Metab. 2013 Mar;24(3):109-19.
- Cohen S, Janicki-Deverts D, Doyle WJ, Miller GE, Frank E, Rabin BS, Turner RB. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci U S A. 2012. 109(16):5995-9.
- Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA. 2007. 298(14):1685-7.
- Cole SW. Social regulation of leukocyte homeostasis: The role of glucocorticoid sensitivity. Brain Behav Immun. 2008. 22:1049–1055.
- D.W. Kufe, J.F. Holland, E. Frei. American Cancer Society Cancer Medicine 6 (6th ed.), 2003. BC Decker, Hamilton, Ont.; Lewiston, NY.
- Da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Inês LB, de Koning EJ, Buttgereit F, Cutolo M, Capell H, Rau R, Bijlsma JW. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis. 2006. 65(3):285-93.
- Derijk RH, Schaaf MJ, Turner G, Datson NA, Vreugdenhil E, Cidlowski J, de Kloet ER, Emery P, Sternberg EM, Detera-Wadleigh SD. A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoidreceptor beta isoform mRNA is associated with rheumatoid arthritis. J Rheumatol. 2001. 28(11):2383-8.
- Dong J, Qu Y, Li J, Cui L, Wang Y, Lin J, Wang H. Cortisol inhibits NF-κB and MAPK pathways in LPS activated bovine endometrial epithelial cells. Int Immunopharmacol. 2018 Jan 20;56:71-77.
- Donn R, Payne D, Ray D. Glucocorticoid receptor gene polymorphisms and susceptibility to rheumatoid arthritis. Clin Endocrinol (Oxf). 2007. 67(3):342-5.
- Fairchild SS, Shannon K, Kwan E, Mishell RI. T cell-derived glucosteroid response-modifying factor (GRMFT): a unique lymphokine made by normal T lymphocytes and a T cell hybridoma. J Immunol. 1984. 132(2):821-7.
- Frank MG, Miguel ZD, Watkins LR, Maier SF. Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide. Brain Behav Immun. 2010. 24(1):19-30
- Grad I, Picard D. The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol. 2007. 275(1-2):2–12.
- Groeneweg FL, Karst H, de Kloet ER, Joels M. Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling. Mol Cell Endocrinol. 2012. 350(2):299–309.
- Heck S., Bender K., Kullmann M., Gottlicher M., Herrlich P., Cato A.C. IκBα-independent downregulation of NF-κB activity by glucocorticoid receptor. EMBO J. 1997. 16:4698–4707.
- Hodges JR, Sadow J. Hypothalamo-pituitary-adrenal function in the rat after prolonged treatment with cortisol. Br J Pharmacol. 1969. 36(3):489-95.
- Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985. 318:635–641
- Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H, Herrlich P. Antitumor promotion and anti-inflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell. 1990 Sep 21;62(6):1189-204. Cell. 1990. 62(6):1189-204.
- Kamba A, Daimon M, Murakami H, Otaka H, Matsuki K, Sato E, Tanabe J, Takayasu S, Matsuhashi Y, Yanagimachi M, Terui K, Kageyama K, Tokuda I, Takahashi I, Nakaji S. Association between Higher Serum Cortisol Levels and Decreased Insulin Secretion in a General Population. PLoS One. 2016. 11(11):e0166077.
- Krieger DT, Allen W, Rizzo F, Krieger HP. Characterization of the normal temporal pattern of plasma corticosteroid levels. J Clin Endocrinol Metab. 1971. 32(2):266-84.
- Kumar R, Thompson EB. Gene regulation by the glucocorticoid receptor: structure : function relationship. J Steroid Biochem Mol Biol. 2005. 94(5):383–94.
- Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, Rainwater K, Ritchie JM, Yang M, Sood AK. Stress related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res. 2003. 9(12):4514-21.
- McEwen B. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 2007. 87:873–904
- Miller GE, Chen E, Sze J, Marin T, Arevalo JM, Doll R, Ma R, Cole SW. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling. Biol Psychiatry. 2008. 64(4):266-72.
- Miller GE, Cohen S, Ritchey AK. Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model. Health Psychol. 2002. 21: 531–541.
- Moreno-Smith M, Lutgendorf SK, Sood AK. Impact of stress on cancer metastasis. Future Oncol. 2010. 6(12):1863-81.
- Nathan C. Points of control in inflammation. Nature. 2002. 420:846–852.
- Philip AM, Daniel Kim S, Vijayan MM. Cortisol modulates the expression of cytokines and suppressors of cytokine signaling (SOCS) in rainbow trout hepatocytes. Dev Comp Immunol. 2012. 38(2):360-7.
- Reichardt HM, Gold R, Lühder F. Glucocorticoids in multiple sclerosis and experimental autoimmune encephalomyelitis. Expert Rev Neurother. 2006. 6(11):1657-70.
- Rosenfeld MG, Glass CK. Coregulator codes of transcriptional regulation by nuclear receptors. J Biol Chem. 2001. 276(40):36865–8.
- Samarasinghe RA, Di Maio R, Volonte D, Galbiati F, Lewis M, Romero G, et al. Nongenomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation. Proc Natl Acad Sci U S A. 2011. 108(40):16657–62.
- Sapolsky RM. Individual difference in cortisol secretory patterns in the wild baboon: rold of negative feedback sensitivity. Endocrinology. 1983. 113(6):2263-7.
- Schernhammer ES, Laden F, Speizer FE, et al. Night-shift work and risk of colorectal cancer in the nurses’ health study. J. Natl Cancer Inst. 2003. 95(11):825–828.
- Seckl JR. 11beta-hydroxysteroid dehydrogenases: changing glucocorticoid action. Curr Opin Pharmacol. 2004. 4(6):597–602.
- Sephton SE, Sapolsky RM, Kraemer HC, et al. Diurnal cortisol rhythm as a predictor of breast cancer survival. J. Natl Cancer Inst. 2000. 92(12):994–1000.
- Shimada T, Hiwatashi N, Yamazaki H, Kinouchi Y, Toyota T. Relationship between glucocorticoid receptor and response to glucocorticoid therapy in ulcerative colitis. Dis Colon Rectum. 1997. 40(10 Suppl):S54-8.
- Sorrells SF, Caso JR, Munhoz CD, Sapolsky RM. The stressed CNS: when glucocorticoids aggravate inflammation. Neuron. 2009. 64(1):33-9.
- Stark JL, Avitsur R, Padgett DA, Campbell KA, Beck FM, Sheridan JF. Social stress induces glucocorticoid resistance in macrophages. Am J Physiol Regul Integr Comp Physiol. 2001. 280(6):R1799-805.
- Steiner RW, Awdishu L. Steroids in kidney transplant patients. Semin Immunopathol. 2011. 33(2):157-67.
- Yang H, Dou W, Lou J, Leng Y, Shen J. Discovery of novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 by docking and pharmacophore modeling. Bioorganic & medicinal chemistry letters. 2008. 18(4):1340–5.