IL-12 is a central player in the regulation of inflammation and immunity, serving as a bridge between innate resistance and adaptive immunity. IL-12 production is important or essential in determining the protective Th1 response against infectious pathogens and tumors, whereas overproduction of IL-12 can result in a series of pathological manifestations, including systemic inflammatory response syndrome, organ-specific autoimmunity, sarcoidosis, vascular lesions, whereas defective production can result in immunodeficiency and allergic situations, including asthma. The study of the molecular mechanisms involved in IL-12 production and function is thus important for the understanding of the physiological role of IL-12 and for the planning of the clinical use of the protein and its genes (in infectious diseases, tumors, severe allergy, or as adjuvants in vaccination) or of antagonists of its production and activity (in autoimmunity, sarcoidosis, etc.). To this end, we propose to: I. Analyze the molecular mechanisms of IL-12 p40 and p35 gene expression; II. Analyze the induction of IL-12 by CD44 signaling in phagocytic cells and the effect of IL-4 and IL-13 on differentiation and production of proinflammatory cytokines by human myelomonocytic and dendritic cells; III. Analyze the mechanisms of acute induction and priming for cytokine production induced by IL-12 and costimulation.
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