Circadian characteristics of permissive and suppressive effects of cortisol and their role in homeostasis and the acute inflammatory response

Abstract

In this work we explore a semi-mechanistic model that considers cortisol's permissive and suppressive effects through the regulation of cytokine receptors and cytokines respectively. Our model reveals the proactive role of cortisol during the resting period and its reactive character during the body's activity phase. Administration of an acute LPS dose during the night, when cortisol's permissive effects are higher than suppressive, leads to increased cytokine levels compared to LPS administration at morning when cortisol's suppressive effects are higher. Interestingly, our model presents a hysteretic behavior where the relative predominance of permissive or suppressive effects results not only from cortisol levels but also from the previous states of the model. Therefore, for the same cortisol levels, administration of an inflammatory stimulus at cortisol's ascending phase, that follows a time period where cytokine receptor expression is elevated ultimately sensitizing the body for the impending stimulus, leads to higher cytokine expression compared to administration of the same stimulus at cortisol's descending phase.

Keywords: Cortisol permissive effects; Cortisol suppressive effects; Cytokine circadian rhythms; Inflammatory response.

Figure 1

Schematic figure of the model. After its rhythmic secretion, cortisol reaches peripheral cell level where it binds to the active form of its two receptors, mineralocorticoid (MR*) and glucocorticoid (GR*) receptors. Cortisol-mineralocorticoid receptor complex (FMR) after its translocation to the nucleus (FMR(N)) induces the expression of cytokine receptors (cortisol’s permissive effects denoted by the blue bold line) whereas cortisol glucocorticoid receptor (FGR) after its translocation to the nucleus (FGR(N)) inhibits the transcription of cytokines (cortisol’s suppressive effects denoted by the red bold line). Cytokine rhythmicity is also regulated by PCGs network through Per/Cry mRNA. PCGs network incorporates the positive and negative feedback loop among Per, Cry, Bmal1 clock genes and CLOCK/BMAL1 heterocomplex [36].

Figure 2

Homeostatic responses of A: cortisol (F_per) and B: pro-inflammatory cytokines (P). Grey lines represent single cell profiles and thick black line denotes their average profile. Experimental data from healthy volunteers have been adopted from [47].

Figure 3

Administration of acute LPS at different times of day (TOD). A: Cortisol (F_per, solid line, left axis) and maximum ensemble pro-inflammatory cytokine levels (maxP_ens, dotted line, left axis) relative to time of day. B: Maximum ensemble pro-inflammatory cytokine levels (maxP_ens) relative to cortisol cortisol levels. Max P_ens was calculated for the 24hr following LPS administration. a, d, z, and n denote cortisol’s ascending, descending, zenith and nadir levels respectively. Grey dot represents the start of nadir (n) phase.

Figure 4

Permissive and suppressive effects of cortisol during the day. A: Cortisol’s permissive (perm, dotted line) and suppressive (sup, solid line) effects relative to time. B: Permissive and suppressive effects relative to cortisol levels (F_per).Permissive profile represents the cortisol mediated induction of cytokine receptors through mineralocorticoid receptor $\left(\frac{k_{fr,2}\cdot \langle FMR\left(N\right)\rangle }{K_{fr,2}+\langle FMR\left(N\right)\rangle }\right)$ whereas suppressive, the cortisol mediated inhibition of cytokines through glucocorticoid receptor $\left(\frac{k_{fr}\cdot \langle FMR\left(N\right)\rangle }{K_{fr}+\langle FMR\left(N\right)\rangle }\right)$. a, d, z, and n denote cortisol’s ascending, descending, zenith and nadir levels respectively. Angle brackets denote average levels.