Can chronic inflammatory cytokine signaling flatten the normal cortisol rhythm?

Pathophysiology of HPA-Axis Feedback Disruption

Chronic systemic inflammation, marked by elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), significantly modulates and disrupts the regulatory feedback loops of the hypothalamic-pituitary-adrenal (HPA) axis. Although acute cytokine exposure typically stimulates HPA activity, chronic exposure induces glucocorticoid receptor (GR) resistance. This occurs through various molecular mechanisms, such as the upregulation of the dominant-negative GRβ isoform (which blocks functional GRα) and reduced cortisol-GR binding affinity. Consequently, the brain and pituitary fail to respond properly to circulating cortisol, impairing the normal negative feedback inhibition that regulates the entire system.

Progression to a Flattened Diurnal Rhythm

This impairment of HPA-axis feedback inhibition directly leads to a flattened diurnal cortisol rhythm. In healthy individuals, cortisol levels follow a distinct 24-hour pattern (with a sharp morning peak and a gradual decline throughout the day) controlled by precise feedback loops. However, when feedback is disrupted, the diurnal curve loses its steepness, resulting in a flatter profile characterized by a failure to appropriately suppress or regulate cortisol release throughout the day.

Association with Reduced Morning Output

A flattened diurnal cortisol curve is strongly associated with a diminished morning surge, specifically a blunted cortisol awakening response (CAR). Large-cohort and chronic stress studies show that individuals with higher inflammatory burdens, such as elevated IL-6 and TNF-α, exhibit significantly lower morning cortisol output alongside flatter daily declines compared to healthy controls.

Bottom line

• Key Takeaway: Chronic pro-inflammatory cytokine signaling drives glucocorticoid receptor resistance, which disrupts HPA-axis negative feedback and ultimately flattens the diurnal cortisol curve, typically presenting as a blunted morning cortisol output and elevated or unstable evening levels.