The cytokine-prostaglandin cascade in fever production: fact or fancy?

Abstract

(1) The classical view of the genesis of infectious fevers is that they develop in sequential steps, starting with the production by peripheral mononuclear phagocytes activated by the infectious noxa (i.e., the invading pathogens and/or their products, e.g., bacterial endotoxic lipopolysaccharides (LPS)) of pyrogenic cytokines, principally tumor necrosis factor-α, interleukin(IL)-1β and IL-6, the release of these cytokines into the bloodstream, their transport to targets accessible from blood (e.g., cerebral microvessels, the organum vasculosum laminae terminalis) in close proximity to the ventromedial preoptic area (VMPO, the presumptive brain site of the febrigenic controller), and the consequent generation of stimulatory signals directed to the VMPO. An alternative view is that the message of the pyrogenic cytokines elaborated in the periphery is conveyed to the VMPO via a neural rather than a humoral pathway. In both views, cyclooxygenase (COX)-2-dependent prostaglandin (PG) E₂ is considered to be the proximal fever mediator induced in the VMPO by these cytokines, modulating the activity of thermosensitive neurons contained in this region and effecting the development of fever. (2) However, peripheral cytokines are not consistently detectable in febrile illnesses, and it was recently reported that neither circulating LPS nor cytokine levels are increased at the onset of robust fevers induced in rats by subcutaneous injections of replicating Escherichia coli. (3) And it was reported long ago that the intracerebroventricular (icv) injection of PGE₂ did not evoke fever in newborn lambs and goats although these animals responded normally to the intravenous injection of LPS, and that the icv-injection of synthetic PGE₂ antagonists that prevented the febrile response of rabbits to icv-injected PGE₂ did not inhibit that to a simultaneously injected endogenous pyrogen. (4) Other, more recent data indicate that the pyrogenic chemokine macrophage inflammatory protein-1β produces fever independently of PGE₂. (5) We found recently that the febrile response of adult guinea pigs to intravenously injected LPS is initiated significantly before the appearance of cytokines in the blood and, moreover, is evoked and sustainable in the absence of preoptic PGE₂. (6) What is amiss? Are the contradictory data fallacious or should the conventional wisdom be revisited? This issue is considered in this article and an explanation suggested for these disparate findings.