Molecular basis of fever in humans

This review presents several areas of research on the pathogenesis of fever in humans and updates new information concerning the role of fever in host defense mechanisms. Fever is mediated by a polypeptide of phagocytic cell origin called leukocytic pyrogen. Several agents and disease processes are associated with the synthesis and release of leukocytic pyrogen. Although the original studies on leukocytic pyrogen suggested that the neutrophil was the primary source, recent experiments indicate the mononuclear phagocyte to be the major producer of leukocytic pyrogen. The mechanism by which human monocytes are stimulated to produce leukocytic pyrogen is discussed, including the effects of corticosteroids, estrogens and antipyretics on the synthesis of leukocytic pyrogen in vitro. The ability of leukocytic pyrogen to alter the hypothalamic thermoregulatory center by increasing arachidonic acid metabolite levels is the most likely mechanism by which leukocytic pyrogen initiates fever. Antipyretics prevent the synthesis of certain cyclooxygenase metabolites, which accounts for their ability to reduce fever. Studies on the chemical and physical properties of human leukocytic pyrogen are reviewed and form the basis for current experiments on the similarities between leukocytic pyrogen and lymphocyte activating factor. These studies suggest that leukocytic pyrogen, in addition to producing fever, also stimulates non-hypothalamic cells involved in aspects of the acute-phase response. In this regard, leukocytic pyrogen may be an important mechanism for host defenses. Hyperthermia may also be beneficial to the host but is distinct from fever; the role of leukocytic pyrogen as well as hyperthermia as a defense mechanism is discussed.