The pituitary gland prevents shock-associated death by controlling multiple inflammatory mediators

Bacterial infections cause a major burden of disease worldwide. Sepsis and septic shock are life-threatening complications of infections. The hypothalamic-pituitary-adrenal (HPA) axis initiates the release of endogenous glucocorticoids that modulate the host stress response and acute inflammation during septic shock. It is an ongoing controversial debate, if therapeutic manipulations of the HPA axis could benefit the clinical situation in the context of shock. Here, we have studied Long Evans rats with hypophysectomy followed by endotoxic shock. The shock-associated lethality was substantially higher in hypophysectomized rats as compared to control mice after cranial sham surgery (7-day survival rates: 27% vs. 89%). Fluorimetric bead-based assays were used to quantify the release of >20 cytokines and chemokines. The surgical removal of the pituitary gland resulted in greatly increased plasma concentrations of mediators such as IL-1α/IL-1β (10-12-fold), TNFα (19-fold), IL-6 (111-fold), IL-10 (10-fold) as well as the Th1 cytokines, Interferon-γ (8-fold), IL-12 (4-fold) and IL-18 (9-fold) after intra-peritoneal lipopolysaccharide (LPS) injections. In contrast, MIP-1α and Leptin were negatively associated with hypophysectomy. The Th2 cytokines, IL-4 and IL-13, as well as G-CSF, VEGF, IP-10 and RANTES were not significantly affected. The gene expression of the IL-6/IL-12 family cytokine, IL-27p28 was profoundly increased after pituitary gland removal followed by endotoxic shock. A dose-dependent reduction of LPS/TLR4-induced IL-27p28 release by glucococorticoids was observed in cultured rodent macrophages (C57BL/6J) as well as in vivo. This study reveals that the neuroendocrine influences of the HPA axis on the shock-associated inflammatory response are more selective and complex than previously known. These findings will be helpful to predict some of the consequences of therapeutic manipulations of the HPA in the context of sepsis and septic shock.