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

• A quantitative model for cortisol's cytokine and cytokine receptor circadian regulation is presented.
• Interplay between cortisol's permissive and suppressive effects is analyzed.
• Time-of-day dependence of acute endotoxin challenge interpreted in the context of cortisol circadian regulation.

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.