PHYSIOLOGIC ROLE OF CYTOKINES IN LIPOPOLYSACCHARIDE

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Intraperitoneal (ip) injection of lipopolysaccharide (LPS) results in many acute phase responses, including the development of fever. It is generally accepted that an ip injection of LPS induces fever by causing a release into the circulation of an endogenous pyrogen (EP), such as interleukin-1 (IL-1), tumor necrosis factor (TNF), interleukin-6 (IL-6), or some other mediator. These EP's are thought to act on the brain to elevate the thermoregulatory set-point. The role of circulating IL-1 (and to a considerably lesser extent TNF and IL-6) in the development of fever has become part of the central dogma regarding the pathogenesis of fever. As a result of the beautiful sequence of indirect experiments that supported this hypothesis over the past 40 years, it is understandable why there has been little impetus to evaluate this hypothesis more directly. It is, however, quite possible that many of the responses currently attributed to IL-1 or to other cytokines will turn out to be "pharmacologic" rather than physiologic or pathophysiologic ones. The purpose of the proposed experiments is to evaluate critically, in the laboratory rat, the degree to which LPS-induced fever actually involves these substances both in the circulation and the brain. The identification of the various putative endogenous pyrogens, the cloning of their specific genes, and the development of specific and sensitive assays for them, now allow the testing of these hypotheses.