G-CSF, but not corticosterone, mediates circulating neutrophilia induced by febrile-range hyperthermia

Abstract

We previously showed that sustained exposure to febrile-range hyperthermia (FRH) for 24 h caused an increase in circulating granulocyte colony-stimulating factor (G-CSF) levels and a peripheral neutrophilia in mice (Hasday J, Garrison A, Singh I, Standiford T, Ellis G, Rao S, He JR, Rice P, Frank M, Goldblum S, and Viscardi R. Am J Pathol 162: 2005-2017, 2003). In this study, we utilized a conscious temperature-clamped mouse model to analyze the kinetics of G-CSF expression and peripheral neutrophil expansion and the contributions of FRH-induced G-CSF expression, glucocorticoid generation, and catecholamine-induced neutrophil demargination. In conscious mice housed at an ambient temperature of 34.5 degrees C, core temperature rapidly equilibrated at 39.5-40 degrees C. Peripheral neutrophil counts increased 2-fold after 24-h exposure to hyperthermia, peaked at 3.6-fold baseline levels after 36-h exposure to FRH, and returned to baseline levels after 42 h of sustained hyperthermia. Plasma G-CSF levels were increased by 6.8-fold after 24 h and peaked at 40-fold baseline levels after 36 h in the hyperthermic mice. Plasma corticosterone levels peaked at 3.3-fold baseline levels after 30-h sustained hyperthermia and returned to baseline by 42 h. Immunoneutralization of G-CSF blocked FRH-induced peripheral neutrophilia, but blockade of the glucocorticoid receptor with mifepristone failed to modify FRH-induced neutrophilia. Epinephrine induced similar increases in peripheral blood absolute neutrophil counts in euthermic mice (2.2-fold increase) and mice exposed to FRH for 36 h (1.8-fold increase). Collectively, these data suggest that FRH-induced expression of G-CSF drives the sustained peripheral neutrophilia that occurs during sustained (36 h) hyperthermia, whereas glucocorticoid generation and catecholamine-induced demargination play little role in this response.

Interpreting Stress Responses during Routine Toxicity Studies

“…In mice, injection of corticosterone at doses approximating short-term stress affects the bone marrow by decreasing lymphoid cell and increasing granulocytic precursors, without affecting erythroid or monocytic cell counts or total cellularity (Laakko and Fraker 2002). Additionally, granulocyte colony stimulating factor (G-CSF) has been shown to modulate increased circulating neutrophil counts due to hyperthermic stress, likely at the level of the bone marrow (Ellis et al 2005). Glucocorticoids also promote survival of neutrophils and apoptosis in eosinophils in circulation (Meagher et al 1996).…”

Core temperature correlates with expression of selected stress and immunomodulatory genes in febrile patients with sepsis and noninfectious SIRS

“…We have previously demonstrated that exposure to FRH (39.5°C) in vitro attenuates TNFα and IL-1β expression in human macrophages (Fairchild et al 2004;Fairchild et al 2000). Exposure to FRH in vivo (core temperature ∼39.5°C) induces G-CSF expression (Ellis et al 2005), and enhances expression of GM-CSF and CXC chemokines in murine models of pulmonary oxygen toxicity (Hasday et al 2003) and Gram-negative pneumonia (Rice et al 2005). Collectively, these studies suggest that febrile-range hyperthermia may modify expression of HSP genes as well as genes that regulate inflammation.…”

Effects of glucocorticoids on the neutrophil count: A cohort study among hospitalized patients

“…However, when the bone marrow is producing granulocytes more quickly, it will also release immature granulocytes into the blood, which is not the case in our study population. Factors like stress, exercise, or infection could cause demargination of neutrophils close to the vessel wall, resulting in an increase in the neutrophil count in peripheral blood, but glucocorticoids are not likely to cause demargination [12,28,36]. Glucocorticoids were found to inhibit neutrophil apoptosis [1,2,[9][10][11].…”