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proximal mediators in the proinflammatory cascade, but they also induce secondary inflammatory mediators such as IL-8, some of the macrophage inflammatory proteins, and the neutrophil adherence proteins (Fong et al., 1990a). Another reason to focus on TNF-a, IL-1, and IL-6 is that the actions of these three proinflammatory cytokines are both overlapping and distinct. These three cytokines affect nearly every organ system in the host. In fact, the original description of TNF-a, IL-1, and IL-6 function was due in large part to military research conducted in the 1970s by the research group at Fort Detrick, led by William R. Beisel and contributed to by Robert Wannemacher, Jr., and Michael Powanda (reviewed in Beisel, 1975, 1977, 1980). These investigators described and examined the functional group of proteins, designated leukocyte endogenous mediator (LEM), in the plasma of animals and patients after inflammatory challenges (Powanda and Beisel, 1982; Wannemacher et al., 1972).

It is now known that those mediators, originally described as LEM or as other functional monikers, including leukocytic pyrogen or endogenous pyrogen, are for the most part one or more of these three proinflammatory cytokines, TNF-a, IL-1, and IL-6. One could argue whether LEM, as originally described by Beisel's group, is IL-1 or whether it is IL-6 or TNF-a, but suffice it to say that these three cytokines are the primary mediators responsible for the induction of the proinflammatory responses to infection and inflammation. It is now recognized that the majority of innate responses to bacterial and viral pathogens, including fever, anorexia, weight loss, trace mineral redistribution, neutrophilia, and hepatic acute-phase protein synthesis among others are mediated by the release of these three proinflammatory cytokines (Beisel, 1980; Dinarello, 1994).

The second problem with discussing proinflammatory cytokines and the utility of their measurements in regard to inflammation or military performance is the dual nature of these cytokines. As several groups showed in the 1970s, the effects of these cytokines are primarily beneficial to the infected host (Kampschmidt and Pulliam, 1975; Kluger et al., 1975), including the stimulation of fever and nonspecific host immunity, the activation of macrophages, the redistribution of trace minerals, the induction of a hepatic acute-phase response, and their role as comitogens or adjuvants for cell-mediated immunity or immunoglobulin production (Beisel, 1975; Kampschmidt, 1983). Although these cytokines are inherently beneficial, they can and do often have adverse effects primarily associated with either their exaggerated production or their continued production. The former occurs in gram-negative septic shock and the disseminated intravascular coagulopathy that accompanies it (Beutler and Cerami, 1986; Dinarello and Wolff, 1993). The latter is associated with some chronic inflammatory syndromes such as AIDS or some neoplasms, or their inappropriate compartmentalized production as occurs in rheumatoid arthritis, and often can lead to devastating pathological consequences.

The challenge, therefore, is how to meaningfully interpret urinary or blood measurements of these cytokines in order to identify the presence and magni-



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