A central challenge in the study of monocyte and macrophage function in the immune system is understanding the early events which regulate their activation. These accessory cells play a major role in antigen processing and presentation, the secretion of several potent polypeptide factors, and the support T lymphocyte proliferation and activation. Several second messenger systems may transmit a variety of stimulatory signals in order to generate an appropriate cellular response, such as the production of specific early-activation gene products. The objective of this proposal is to further the understanding of monocyte/macrophage activation through the study of nuclear regulatory proteins which transduce stimulatory signals and control the expression of early-activation genes. Experiments will focus on the expression of the monokines interleukin 1alpha (IL-1alpha) and interleukin 1beta (IL-1beta as a model system for the study of early events in monocyte activation. These important immunoregulatory polypeptides are candidates for the study of early events since they are rapidly and coordinately expressed following monocyte/macrophage stimulation. The long-range goals of these studies are (1) to identify and purify the nuclear regulatory proteins which modulate IL-1 expression, (2) to evaluate the functional role of these proteins, (3) to determine how macrophage activating factors such as gamma interferon and colony stimulating factors can augment IL-1 expression through effects on these nuclear proteins, and (4) to examine how their activity is regulated by second messenger signals and/or specific intracellular inhibitors. These studies should lead to a greater understanding of the mechanism by which various stimulatory signals are utilized by the macrophage/monocyte to generate specific DNA-protein interactions and lead to the initiation of specific early events during activation. This information has particular value in understanding the etiology of several autoimmune and inflammatory diseases which may involve the aberrant expression of monokines. Furthermore, the activation of HIV-infected macrophages can lead to the co-expression of both viral gene products and IL-1, thus an understanding of the early events which regulate IL-1 expression may shed light on the pathology of HIV-infected macrophages.
