The hypothesis that fever is initiated by the action of the polypeptide leukocytic pyrogen (LP) on the thermoregulatory system is well established; however, considerable evidence now supports the concept that LP also mediates several aspects of the acute phase response and plays an essential role in lymphocyte function. Purification and characterization of LP using fever as well as lymphocyte proliferation and other biological assays have been unable to separate these activities, and the term interleukin-1 (IL-1) has been adopted to denote the activity and hormonal nature of this molecule. Continued investigation is indicated on the biological activities and structure-function relationship of LP. Experiments will focus on large scale production of LP from human monocytes and the histocytic lymphoma line U937 stimulated with the potent LP-inducer, toxic shock toxin. Purification and amino acid sequence studies of LP are included since large scale production and purification schemes have been established. Data from sequence studies are vital to understanding the nature of LP and its effects on the host. Using intrinsic labeling of LP with radioactive amino acids, purification can be monitered and important studies on cell receptors initiated. Specific receptors for LP have not been identified and experiments are designed to use intrinsically labeled, purified human LP to locate areas in the hypothalamus which bind LP. Also, receptor identification on T-cells and human neutrophil membrane vesicles will be undertaken. Demonstrating LP binding to these cells and membranes provides the basis for receptor identification. Despite increasing evidence for the role of LP in mediating several components of the acute phase response, the mechanism by which this molecule affects so many different cell types remains unclear. Therefore, fundamental studies on the ability of LP to act as a calcium ionophore and inducer of arachidonic acid release are included. The role of LP in human disease requires studies on in vitro production and improved biological and immunoassays; recent progress has shed new light on how best to approach detection systems in human body fluids during health and disease. Also included in this proposal are the recovery and characterization of LP in the drainage fluid from patients on peritoneal dialysis and experiments to determine how this procedure stimulates LP production in vivo. The overall purpose of these studies is to link the production of LP to its actions on various host tissues.
Showing the most recent 10 out of 565 publications
