Exposure to febrile temperature modifies endothelial cell response to tumor necrosis factor-α

Abstract

Fever is an important regulator of inflammation that modifies expression and bioactivity of cytokines, including tumor necrosis factor (TNF)-α. Pulmonary vascular endothelium is an important target of TNF-α during the systemic inflammatory response. In this study, we analyzed the effect of a febrile range temperature (39.5°C) on TNF-α-stimulated changes in endothelial barrier function, capacity for neutrophil binding and transendothelial migration (TEM), and cytokine secretion in human pulmonary artery endothelial cells (EC). Permeability for [14C]BSA tracer was increased by treatment with TNF-α, and this effect was augmented by incubating EC at 39.5°C. Treating EC with 2.5 U/ml TNF-α stimulated an increase in subsequent neutrophil adherence and TEM. Incubating EC at 39.5°C caused a 30% increase in TEM but did not modify the enhancement of neutrophil adherence or TEM by TNF-α treatment. Analysis of cytokine expression in EC cultures exposed to TNF-α at either 37° or 39.5°C revealed three patterns of temperature and TNF-α responsiveness. Granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-8 were not detectable in untreated EC but were increased after TNF-α exposure, and this increase was enhanced at 39.5°C. IL-6 expression was also increased with TNF-α exposure, but IL-6 expression was lower in 39.5°C EC cultures. Transforming growth factor-β1was constitutively expressed, and its expression was not influenced either by TNF-α or exposure to 39.5°C. These data demonstrate that clinically relevant shifts in body temperature might cause important changes in the effects of proinflammatory cytokines on the endothelium.