For many years, it was thought that bacterial products caused
fever via the intermediate production of a host-derived,
fever-producing molecule, called
endogenous pyrogen (EP). Bacterial products and other
fever-producing substances were termed exogenous
pyrogens. It was considered highly unlikely that exogenous
pyrogens caused
fever by acting directly on the hypothalamic thermoregulatory center since there were countless
fever-producing microbial products, mostly large molecules, with no common physical structure. In vivo and in vitro,
lipopolysaccharides (LPSs) and other microbial products induced EP, subsequently shown to be
interleukin-1 (IL-1). The concept of the '
endogenous pyrogen' cause of
fever gained considerable support when pure, recombinant
IL-1 produced
fever in humans and in animals at subnanomolar concentrations. Subsequently, recombinant
tumor necrosis factor-alpha (
TNF-alpha),
IL-6 and other
cytokines were also shown to cause
fever and EPs are now termed pyrogenic
cytokines. However, the concept was challenged when specific blockade of either
IL-1 or TNF activity did not diminish the febrile response to LPS, to other microbial products or to natural
infections in animals and in humans. During
infection,
fever could occur independently of
IL-1 or TNF activity. The
cytokine-like property of
Toll-like receptor (TLR) signal transduction provides an explanation by which any microbial product can cause
fever by engaging its specific TLR on the vascular network supplying the thermoregulatory center in the anterior hypothalamus. Since
fever induced by
IL-1,
TNF-alpha,
IL-6 or TLR
ligands requires
cyclooxygenase-2, production of
prostaglandin E2 (
PGE2) and activation of hypothalamic
PGE2 receptors provides a unifying mechanism for
fever by endogenous and exogenous
pyrogens. Thus,
fever is the result of either
cytokine receptor or TLR triggering; in
autoimmune diseases,
fever is mostly
cytokine mediated whereas both
cytokine and TLR account for
fever during
infection.