Acute induction and priming for cytokine production in lymphocytes.
When T-lymphocytes (CD4+, CD8+, or TCR gamma delta +) and NK cells proliferate in vivo or in vitro in response to exposure to antigen or other stimuli, they often segregate into subsets with the ability to produce either type-1 [interferon-gamma (IFN-gamma) and interleukin-2 (IL-2)] or type-2 cytokines (IL-4, IL-5, IL-6 and IL-10). IL-12 induces the differentiation of type-1 cytokine-producing T-cells primarily through its ability to prime them for high IFN-gamma production; however, paradoxically IL-12 also primes T-cells for high production of the type-2 cytokine IL-10. Priming of T-cells for IL-4 production requires the presence of IL-4, but it is maximally observed in cultures containing both IL-4 and IL-12. IL-12, in addition to priming T-cells for high IFN-gamma and IL-10 production, is also a potent acute inducer of expression of the IFN-gamma gene in T- and NK-cells, and, to a much lower extent, of the IL-10 gene. IL-4, which has a very powerful effect in priming T-cells for IL-4 production, does not appear to have a significant ability to directly activate the expression of the IL-4 gene. Thus, IL-12 and IL-4 affect the expression of type-1 and type-2 cytokine genes by two different mechanisms: an acute induction of gene expression which is rapid and reversible, and a priming of the genes to a highly responsive state to restimulation, a state that is stable and probably irreversible.
Wistar Institute, Philadelphia, PA 19104, USA. trinchieri@wista.wistar.upenn.edu
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Trinchieri
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Peritt
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D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma