For more than 50 years, experimental studies on
fever have focused on a substance from leukocytes called leukocytic or
endogenous pyrogen. Various investigators concluded that changes associated with
infection--such as numbers of circulating leukocytes; levels of trace metals,
amino acids, and hepatic
proteins; and altered lymphocyte function--were also caused by endogenous leukocyte mediators. There was reasonable evidence that
fever and these other changes were brought about through the action of a single
endogenous pyrogen, now known as
interleukin 1 (IL-1). Two forms of
IL-1 have been cloned (IL-1 beta and IL-1 alpha), and studies of recombinant
IL-1 preparations have confirmed that
fever and the broad spectrum of host responses to
infection and injury are indeed mediated by this substance. However,
IL-1 is not the only leukocyte product that induces
fever:
tumor necrosis factor (
cachectin) and
interferon produce
fever in humans and animals. Accordingly, the concept of a single
endogenous pyrogen now requires modification. Nature has conferred the ability to produce
fever on no fewer than three structurally distinct molecules. Investigators trying to determine what triggers the hypothalamus to initiate
fever in a particular disease must now consider these three endogenous
pyrogens, either alone or together, as mediators of
fever.