Infected adults characteristically exhibit, in addition to fever, a concatenation of nonspecific host responses, termed the acute-phase reaction (APR). These include: neutrophilic leukocytosis, changes in the concentrations of certain plasma proteins and trace metals, and various other associated adjustments. It has long been known that the fever of infection is mediated by an endogenous factor from macrophages/monocytes, called Interleukin I (IL1). During the past decade, evidence has accumulated indicating that the nonthermal components of the APR also are mediated by IL1. It is well established that the primary site of the febrile action of IL1 is the preoptic are (PO) of the hypothalamus. Subsidiary IL1-sensitive sites that can drive fever have been localized in the lateral hypothalamus, pons, and medulla. Recent results from my laboratory indicate that the PO also is involved importantly in the regulation of certain nonthermal acute-phase responses to IL1, in particular the hepatic synthesis of glycoproteins. The data further suggest that the preoptic units that activate the febrile and nonfebrile responses to IL1 may be distinct. These proposed studies, therefore, are directed toward analyzing further the neural systems in the PO mediating the acute-phase reaction. Specifically, they are designed to determine whether the monoamines and the opioids, two classes of neurochemical substances with possible roles in fever production, might also be implicated in the control of the nonthermal acute-phase reaction. Subsequently, studies will be undertaken to determine whether identified extra-PO, IL1-sensitive febrigenic sites similarly can drive the nonfebrile APR, and whether they do so through the same transmitters as the PO. The results should permit differentiating among responses that might be activated by IL1 at different loci within the brain and provide information toward understanding the mode of action of IL1 in the induction of fever and other acute-phase host defense responses.
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