Endocrine Abstracts

Background: Cortisol is an essential steroid hormone released from the adrenal gland. Plasma cortisol levels follow a circadian rhythm under the control of the Hypothalamic–Pituitary–Adrenal axis, reaching peak levels in the morning. Cortisol has long been known to exert immunosuppressive effects and accordingly, glucocorticoids are central in treating inflammatory disease. Cortisol’s propensity to downregulate certain pro-inflammatory cytokines and upregulate other anti-inflammatory cytokines is well-established. However, there remain gaps in our mechanistic understanding of how cortisol modulates various cytokines. Historically, studies have focussed on a small number of relatively well-established cytokines yet the effect of cortisol on many other cytokines remains uncertain.

Methods: Leveraging data from the CORtisol NETwork (N=25 314) and FINRISK (N=8293) genome-wide association studies, we used two-sample Mendelian Randomisation (MR) to investigate the causal effect of genetically proxied increased morning cortisol levels on 42 circulating cytokines. MR utilises genetic variants in an instrumental variable framework to make causal inferences. By virtue of Mendel’s Law of Segregation and Law of Independent Assortment, the inheritance of genetic variants is random. Furthermore, germline genetic variation corresponding to levels of morning cortisol and circulating cytokines is non-modifiable by the environment and temporally precedes the onset of clinically detectable changes in circulating cytokine levels. Thus, under specific assumptions, MR offers a method of investigating the causal effect of a morning cortisol on a comprehensive range of cytokines that is less vulnerable to confounding and reverse causation biases in comparison to traditional observational studies.

Results: Increased genetically proxied morning cortisol levels were associated with reduced levels of Interleukin 8 (IL-8) and increased levels of Macrophage Migratory Inhibitory Factor (MIF). A 1 S.D. increase in genetically proxied morning cortisol levels corresponded to a 0.767 normalised SD-unit decrease in IL-8 (P=1.14×10⁻⁴, 95% CI =−1.157 to −0.378) and a 0.806 normalised SD-unit decrease in MIF (P=3.68×10⁻⁵, 95% CI =−1.189 to −0.423). These findings remained statistically significant after applying the Bonferroni correction for multiplicity.

Conclusions: These results provide mechanistic insight into the immunomodulatory effects of cortisol. Clinically, our findings underline the therapeutic importance of steroids in inflammatory conditions where IL-8 and MIF play central roles in the pathophysiology of disease, e.g. Inflammatory Bowel Disease, Rheumatoid Arthritis and Systemic Lupus Erythematosus. Moreover, IL-8 and MIF may represent alternative therapeutic targets in these conditions, which could avoid some of the adverse effects of long-term glucocorticoid therapy.