Reduction of the expression and production of adhesion molecules and chemokines by brain endothelial cells in response to tumor necrosis factor-α and interleukin-17 in hypothermia

Abstract

Objective The upregulation of adhesion molecules and chemokines might facilitate the recruitment and infiltration of inflammatory cells into injured brain tissue, leading to enhanced post-ischemic brain inflammation and exacerbated brain injury. Here we examined the effects of hypothermia and hyperthermia on the expression and production of adhesion molecules and chemokines by brain endothelial cells in response to tumor necrosis factor (TNF)-α and interleukin (IL)-17 in an attempt to identify the mechanisms responsible for the neuroprotection conferred by therapeutic hypothermia. Methods Brain endothelial bEnd.3 cells were stimulated with TNF-α or IL-17 under hypothermia (33°C), normothermia (37°C) or hyperthermia (39°C). Levels of mRNA expression and protein production of a number of adhesion molecules and chemokines were measured. Results In TNF-α-stimulated bEND.3 cells, the mRNA expression of adhesion molecules, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 was reduced by hypothermia compared with normothermia. The production of chemokines, macrophage inflammatory protein-2 (MIP-2/CXCL2), interferon-γ-inducible protein-10 (IP-10/CXCL10) and monocyte chemoattractant protein-1 (MCP-1/CCL2) was reduced by hypothermia, but augmented by hyperthermia. In IL-17-stimulated bEND.3 cells, the mRNA expression of IP-10/CXCL10, and the production of MIP-2/CXCL2 and MCP-1/CCL2 were reduced by hypothermia compared with normothermia. Conclusions Therapeutic hypothermia might suppress the recruitment of inflammatory cells to the central nervous system by directly reducing the expression and production of cell adhesion molecules and chemokines by brain endothelial cells in response to stimulation with TNF-α and IL-17. Conversely, the hyperthermic state might promote such inflammatory responses by directly augmenting the TNF-α-stimulated brain endothelial cell production of chemokines.