IL-1beta was identified after a long search for the
endogenous pyrogen. It acts by inducing synthesis of
prostaglandin E2, which mediates the late phase of IL-1beta-induced
fever. Here we show by radiotelemetry that the early phase of the
fever response to IL-1beta is mediated by
ceramide. Hypothalamic application of the cell-penetrating
C2-ceramide mimics the rapid phase of the IL-1beta-induced
fever. Inhibition of
ceramide synthesis blocks the rapid phase of
fever but does not affect the slower
prostaglandin E2-dependent phase, which is blocked by
indomethacin or by null mutation of the
EP3 prostanoid receptor. Electrophysiological experiments on preoptic area/anterior hypothalamic neurons show that
C2-ceramide, but not
dihydroceramide, mimics the rapid hyperpolarizing effects of IL-1beta on the activity of warm-sensitive hypothalamic neurons. IL-1beta-mediated hyperpolarization is blocked by PP2, the selective inhibitor of the
protein tyrosine kinase Src, which is known to be activated by
ceramide. These in vivo and in vitro data suggest that
ceramide fulfills the criteria for an
endogenous pyrogen.