The response of the organism to infectious agents involves a complex interaction of different cell types, which are often regulated in their function by a network of soluble factors or cytokines. Cytokine response is instrumental in regulating inflammation, migration and functional activation of effector cells of natural resistance, as well as differentiation, proliferation and activation of the T and B lymphocytes, the effector cells of cellular and humoral adaptive immunity. NK cell stimulatory factor or interleukin 12 (NKSF/IL-12) is a novel heterodimeric cytokine, that is produced by phagocytic cells and B cells and acts on T cells and NK cells by inducing production of lymphokines, particularly interferon-y (IFN-y), proliferation, and enhancement of specific and non- specific cytotoxic activity. Preliminary evidence suggests a role for NKSF/IL-12 in endotoxin shock and in regulation of T helper (TH) 1 versus Th2 immune responses. On the basis of these studies, it is proposed that NKSF/IL-12 by providing a signaling bridge between phagocytic cells and lymphocytes plays a key role in regulation of inflammation and immune response. In order to analyze this hypothesis, the mechanisms of regulation of NKSF/IL-12 production will be analyzed by characterizing the cells in human peripheral blood and other organs as well as the human cell lines able to express mRNA for the two chains of NKSF/IL-12 and to produce NKSF/IL-12 proteins in response to various stimulatory and inhibitory stimuli and by studying the transcriptional or posttranscriptional molecular mechanisms involved in the regulation of NKSF/IL-12 production. The biological effects of NKSF/IL-12 on T lymphocytes and NK cells will also be investigated by studying a) the ability of the NKSF/IL-12 heterodimer to interact with surface receptors, mediate signal transduction, and regulate expression of genes encoding proteins important in lymphocyte differentiation, proliferation, and functions; b) the mechanisms of regulation of the IFN-y gene by NKSF/IL-12; and c) the role of NKSF/IL-12 in regulating differentiation of human TH1 and TH2 cells.
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