Several hypotheses have been put forth to describe how production of the cytokine interleukin 1β (IL-1β) in the periphery induces fever, including activation of neurons and microglia, direct stimulation of hypothalamic neurons and peripheral activation of the vagus nerve.

Now, Markus Schwaninger and his colleagues (J. Exp. Med. 208, 2615–2623) report that brain endothelial cells are the target of IL-1β in fever. In vitro IL-1β activates the MAP kinase kinase kinase TAK1. This induces cyclooxygenase-2 and results in prostaglandin E2 production in brain endothelial cells, leading to fever and lethargy. Conditional deletion of TAK1 specifically in brain endothelial cells in mice reduced the IL-1β–induced fever response and lethargy. TAK1 ablation in neurons, astrocytes and oligodendrocytes did not alter this response, ruling out a contribution by these cell types.

In addition to fever and lethargy, the IL-1β–induced sickness response also includes anorexia, weight loss and activation of the hypothalamic-pituitary axis in mice. However, these latter characteristics were not affected by TAK1 deletion in brain endothelial cells, suggesting that IL-1β may affect different elements of the sickness response by acting on distinct cell populations.