Function and dysfunction of the hypothalamic-pituitary-adrenal axis in inflammation. (A) Activation of the hypothalamic-pituitary-adrenal (HPA) axis and negative feedback regulation. The central circadian oscillator and different stressors (physical, emotional, fever, hypoglycemia, or hypotension) during physiological stress reactions trigger the hypothalamus to release corticotropin-releasing hormone (CRH). CRH acts on the anterior pituitary and induces release of adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal gland to produce and release cortisol. Cortisol exhibits its known metabolic effects (mainly provision of glucose and energy), which serve to counteract the stressor. Inflammation can also trigger the HPA axis. In the physiological regulation of the HPA axis, cortisol release is terminated by negative feedback regulation of cortisol on the hypothalamus and anterior pituitary. Synthetic glucocorticoids (GCs) applied in GC therapy can cause negative feedback regulation. This can lead to adrenal suppression. (B) A new concept for the feedback loop: the hepato-hypothalamic-pituitary-adrenal-renal axis. The HPA axis is extended by GC metabolism: cortisol is converted to cortisone mainly by the kidney, via 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, in order to protect the nonspecific mineralocorticoid receptor from activation by cortisol. The major organ for converting cortisone to cortisol is the liver, via 11β-HSD1. In chronic inflammation, conversion from cortisone to cortisol by 11β-HSD1 is increased (reviewed in ). This may amplify negative feedback and explain HPA dysfunction in inflammation. SERVIER medical art images were used for generation of figures.