Prostaglandin E2 in the Pathogenesis of Fever: An Updatea

ABSTRACT: Prostaglandin E 2 (PGE 2 ) is recognized as a key intermediate in the sequence of events leading to fever. Normally undetectable or barely detectable in brain, it rises selectively on exposure to an infectious noxa and the attendant generation of pyrogenic cytokines outside and, in the case of interleukin (IL)‐6, inside the brain. The mechanism by which pyrogens in the circulation promote the appearance of PGE 2 within the confines of brain is not clear, and it is not known how PGE 2 activation is selective with IL‐6 being induced in brain. We have found that the cerebral microvasculature is not suitable as a source of PGE 2 in response to blood‐borne pyrogens. In addition, we show that IL‐6 differs from other pyrogens in being able to stimulate specifically PGE 2 synthesis. Nevertheless, brain‐derived IL‐6 does not appear to be necessary for PGE 2 activation and the attendant fever. We conclude that signal‐transducing mechanisms operating across the blood‐brain barrier are most critical for the development of the febrile reponse to a systemic noxa.