Macrophages play critical roles not only in cell-mediated immune responses to microbial infection but also in diverse non-septic inflammatory reactions such as occur in cancer, osteoarthritis, vasculitis, encephalitis,and diabetes. The objective of this project is to determine the role of T cell cognate interactions in signaling activation of macrophage effector functions. The role of both antigen specific and antigen nonspecific interactions will be examined. The role of T cell derived noncognate signals, such as IFN-gamma and IL-10, in modulating the effects of the cognate signals will also be considered. Recent evidence suggests that a cascade of signals is required for the induction of macrophage effector activities, such as generation of reactive nitrogen intermediates. Separate signal pathways may be involved in the induction of synthesis of inflammatory cytokines such as IL-1 and TNF-alpha, in the activation of the cytokine secretory machinery, and in induction of receptors for these and other cytokines. Events in macrophage activation that will be examined include induction of early activation genes such as myc, fos, and KE, induction of cytokine production, and induction of nitric oxide generation. Induction of cytokine production will be assayed by DNA-RNA hybridization and by immunoprecipitation of extracellular and intracellular cytokine. This will allow an assessment of degree of cytokine gene transcription, translation, and posttranslational processing and secretion. Subsequent studies will focus on the signal transduction pathways involved in cognate and noncognate signaling.
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