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G W Duff

Publications and source records attributed to G W Duff.

132 records · Page 8Linked to original sources
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The pyrogenic and mitogenic actions of interleukin-1 are related.

Our present understanding of the pathogenesis of fever is that host macrophages, following activation by an appropriate stimulus such as Gram-negative lipopolysaccharide (LPS) immune complexes, or primed lymphocytes in the presence of specific antigen, synthesize and release endogenous pyrogen (EP). EP is carried in the blood circulation to the hypothalamic area of the brain where its action, involving a protein synthetic step, results in an increase of the level at which body temperature is maintained. Recently, it was shown that EP is very similar and possibly identical to another macrophage mediator previously called lymphocyte activating factor and now known as interleukin-1 (IL-1) which, in conjunction with lectin or specific antigen, induces clonal expansion of T lymphocytes. We show here that murine T-cell proliferation in response to IL-1 in vitro is greatly increased when the cells are exposed to a temperature typical of fever and that injection of the same IL-1 causes fever in mice. If this relationship exists in vivo, the resulting facilitation of a T-cell-dependent immune response may well confer survival value and contribute to the evolutionary conservation of fever--a phylogenetically ancient response to infection.

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Studies on the production of endogenous pyrogen by rabbit monocytes: the role of calcium and cyclic nucleotides.

Rabbit monocytes stimulated with endotoxin produced endogenous pyrogen, even under conditions of high or low extracellular calcium concentrations. Maximal production occurred when the concentration was in the near-physiological range. Prolonged incubation of cells with a calcium chelator prevented subsequent activation with endotoxin, an effect which was rapidly reversible by re-addition of calcium but not other cations. Addition of small amounts of lanthanum, which acts as a calcium channel blocker, prevented the restoration of pyrogen production, indicating that entry of the added calcium into the monocyte was required. Incorporation of a calcium ionophore into the cell membrane did not stimulate pyrogen production, and no measurable influx or efflux of calcium occurred during stimulation with endotoxin. These observations suggest that a slowly exchangeable calcium pool is necessary for the production of endogenous pyrogen, but that a rise in intracellular calcium is not by itself a necessary or sufficient stimulus. This stands in contrast to other biological systems in which Ca2+ directly couples stimulus and hormone secretion. Incubation of cells with agents shown to increase cyclic 3',5' AMP or cyclic 3',5' GMP levels in monocytes similarly did not stimulate pyrogen production or modulate its production by endotoxin stimulation. Thus, cyclic nucleotides also did not play a detectable role as intracellular messengers in this system. Future work is required to define more clearly the mechanism for the production of endogenous pyrogen, given its marked effects on the immune system through lymphocyte activation and temperature regulation.

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Is fever beneficial to the host: a clinical perspective.

Fever is a phylogenetically ancient host response to infection, being found in fish and lizards, and conserved, with all its metabolic costs, in the higher mammals, including man. The conservation of the fever response in evolution is used as an argument for its survival value and, indeed, in experiments with cold-blooded animals "behavioral fever" has been demonstrated to reduce mortality associated with infection. Recent advances in the biology of interleukin-1 and other cytokines have allowed the testing, in vitro, of components of mammalian host defense (such as immune cell function) at temperatures typical of fever, and marked effects have been found. It remains to be demonstrated, however, that the hyperthermia of fever has survival value in man, and though it might be predicted that fever would be beneficial in infections, it is quite possible that in some circumstances even mild fever could be construed as harmful. In autoimmunity, for example, increased T-cell activation at febrile temperatures may well accelerate disease progress.

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Fever and immunoregulation: hyperthermia, interleukins 1 and 2, and T-cell proliferation.

The role of fever in host defense, if indeed it has one, is poorly understood. Fever in response to exogenous agents is mediated by a host macrophage product called endogenous pyrogen (EP). Recently it has been shown that EP is probably identical to interleukin 1 (IL1), an immunostimulatory macrophage product that induces T-cell proliferation. We postulated that the pyrogenic and immunostimulatory actions of this host mediator might be interrelated and tested T-cell proliferation induced by IL1 at a temperature characteristic of fever. The T-cell proliferative response to IL1 (and to the lymphokine, interleukin 2) was greatly increased at 39 degrees C compared to 37 degrees C, while B-cell mitogenesis in response to lipopolysaccharide was not. These findings suggest that, if similar events occur in vivo, fever may have important immunoregulatory significance and call into question the current indiscriminate use of antipyretic agents.

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