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Fever is a cardinal symptom of infectious or inflammatory insults, but it can also arise from noninfectious causes. The fever-inducing agent that has been used most frequently in experimental studies designed to characterize the physiological, immunological and neuroendocrine processes and to identify the neuronal circuits that underlie the manifestation of the febrile response is lipopolysaccharide (LPS). Our knowledge of the mechanisms of fever production and lysis is largely based on this model. Fever is usually initiated in the periphery of the challenged host by the immediate activation of the innate immune system by LPS, specifically of the complement (C) cascade and Toll-like receptors. The first results in the immediate generation of the C component C5a and the subsequent rapid production of prostaglandin E2 (PGE2). The second, occurring after some delay, induces the further production of PGE2 by induction of its synthesizing enzymes and transcription and translation of proinflammatory cytokines. The Kupffer cells (Kc) of the liver seem to be essential for these initial processes. The subsequent transfer of the pyrogenic message from the periphery to the brain is achieved by neuronal and humoral mechanisms. These pathways subserve the genesis of early (neuronal signals) and late (humoral signals) phases of the characteristically biphasic febrile response to LPS. During the course of fever, counterinflammatory factors, "endogenous antipyretics," are elaborated peripherally and centrally to limit fever in strength and duration. The multiple interacting pro- and antipyretic signals and their mechanistic effects that underlie endotoxic fever are the subjects of this review.

It is now well recognized that the body temperature of older men and women is lower than that of younger people and that their tolerance of thermal extremes is more limited. The regulation of body temperature does not depend on a single organ, but rather involves almost all the systems of the body, i.e. systems not exclusively dedicated to thermoregulatory functions such as the cardiovascular and respiratory systems. Since these deteriorate naturally with advancing age, the decrement in their functions resonates throughout all the bodily processes, including those that control body temperature. To the extent that the age-related changes in some of these, e.g. in the musculoskeletal system, can be slowed, or even prevented, by certain measures, e.g. fitness training, so can the decrements in thermoregulatory functions. Some deficits, however, are unavoidable, e.g. structural skin changes and metabolic alterations. These impact directly on the ability of the elderly to maintain thermal homeostasis, particularly when challenged by ambient thermal extremes. Since the maintenance of a relatively stable, optimal core temperature is one of the body’s most important activities, its very survival can be threatened by these disorders. The present article describes the principal, age-associated changes in physiological functions that could affect the ability of seniors to maintain their body temperature when exposed to hot or cold environments.

Recent data suggest that fever may be initiated by products of liver macrophages that activate subdiaphragmatic vagal afferents. In the brain, these inputs may be transmitted to fever-producing sites via noradrenergic pathways;prostaglandin E2 may be the ultimate pyrogenic mediator.