Fever is a common symptom of infectious and inflammatory disease. It is well established that prostaglandin E2 is the final mediator of fever, which by binding to its EP3 receptor subtype in the preoptic hypothalamus initiates thermogenesis. Fever is a cardinal response to infection that has been conserved in warm and cold-blooded vertebrates for over 600 million years of evolution. The fever response is a hallmark of infection and inflammatory disease and has been shaped through hundreds of millions of years of natural selection.
Over the years, several different hypotheses emerged on how peripheral immune signals could traverse, or circumvent, the blood-brain barrier to influence the brain and elicit fever. These hypotheses include direct pyrogen action on the organum vasculosum of the lamina terminalis, activation of cells in the blood-brain barrier, transfer of blood-borne prostaglandin E2 (PGE2) into the brain, and activation of peripheral nerves by immune signals.
Temperature is ultimately regulated in the hypothalamus. A trigger of the fever, called a pyrogen, causes release of prostaglandin E2 (PGE2). PGE2 in turn acts on the hypothalamus, which creates a systemic response in the body, causing heat-generating effects to match a new higher temperature set point.
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