Pharmacological corticosterone suppresses pro-inflammatory cytokine gene expression in a tissue-dependent manner independent of sleep fragmentation in male mice.

Abstract

Disrupted sleep from obstructive sleep apnea or insomnia promotes an inflammatory environment. Studies in mice have shown that experimental sleep fragmentation (SF) increases pro-inflammatory cytokine gene expression in the brain and peripheral tissues as well as increases circulating glucocorticoids. Although glucocorticoids classically exert anti-inflammatory effects at pharmacological concentrations, they may also modulate immune function in a context- and dose-dependent manner. To investigate whether glucocorticoids regulate pro-inflammatory responses, we used a classical adrenalectomy (ADX) ablation and corticosterone (CORT) replacement design. Adult male C57BL/6J mice received bilateral ADX, sham surgery, or ADX with CORT replacement in drinking water and were exposed to acute (24 h) SF or no SF (NSF). Pro-inflammatory gene expression (interleukin-1 beta and tumor necrosis factor-alpha) was quantified in the hippocampus, hypothalamus, and prefrontal cortex, as well as peripheral tissues including the liver, spleen, heart, and epididymal white adipose tissue. ADX effectively reduced serum CORT, while CORT replacement produced pharmacological hormone levels. Pharmacological CORT treatment robustly suppressed pro-inflammatory gene expression across multiple brain regions (prefrontal cortex, hypothalamus) and peripheral tissues (liver, heart, spleen) compared with ADX and/or sham mice, indicating a strong anti-inflammatory effect at elevated glucocorticoid concentrations. In contrast, ADX mice showed modest, tissue-specific increases in inflammatory gene expression, primarily in the liver and heart, suggesting limited regulation by physiological CORT levels. SF did not significantly increase pro-inflammatory gene expression compared with controls. In conclusion, CORT exerts potent, dose-dependent, and tissue-specific suppression of pro-inflammatory gene expression that is not modulated by acute SF in male mice.