Fever: Cytokines and Prostaglandins Cause the Sickness Response

There are several processes by which invading infectious organisms can set off the sickness response. One is that they can act locally on white blood cells that then produce circulating hormones called cytokines. The cytokines can have direct actions on certain types of neurons, but most of the “sickness response” is due to the cytokines (or certain components of invading bacteria themselves) inducing white blood cells and vascular endothelial cells to make prostaglandins. The primary role of prostaglandins in the sickness responses is demonstrated by the fact that inhibitors of cyclooxygenase, the enzyme that produces prostaglandins, is sufficient to prevent most of these responses.

Prostaglandins can act on receptors on peripheral nerves, but they also can cross the blood-brain barrier and act directly on brain neurons that express prostaglandin receptors. The prostaglandin that is probably most important for causing sickness responses is prostaglandin E2 (PGE2), and it has a series of four different E-type prostaglandin receptors (EP receptors) that are found on different classes of cells in the central nervous system (CNS). For example, EP3 receptors in the median preoptic nucleus recognize PGE2 during an inflammatory response and are critical for causing a fever response. Activation of corticosteroid secretion during a sickness response requires EP3 receptors in the preoptic area and the ventrolateral medulla, as well as EP1 receptors, which may be in the paraventricular hypothalamic nucleus or the central nucleus of the amygdala. Increased sensitivity to pain during fever is likely to be due to EP3 receptors, but the exact locus of those receptors is not yet known.

The fever response during sickness appears to be due to neurons in the median preoptic nucleus withdrawing γ-aminobutyric acid (GABA)ergic inhibition of the neurons in the paraventricular and dorsomedial hypothalamic nuclei and the medullary raphe that produce elevated body temperature. This allows body temperature to rise by about two to three degrees centigrade. Fever in the range of 39° C to 40° C is uncomfortable but may be an adaptive response to help fight off invading organisms.

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