Induction of interleukin-12/p40 by superantigens in macrophages is mediated by activation of nuclear factor-kappaB.
Multimerization of the MHC class II molecule by superantigens results in activation of cellular signal transduction pathways in macrophage and B cells. Here we show that superantigen staphylococcal enterotoxin B (SEB) induces IL-12/p40 secretion in macrophages. SEB-induced expression of the IL-12/p40 gene involves activation and nuclear translocation of nuclear factor kappaB (NF-kappaB). The NF-kappaB heterodimer bound to the NF-kappaB consensus sequence of the IL-12/p40 gene promoter is p50/C-Rel. Inhibition of PKC and PKA activation results in suppression of activation and translocation of NF-kappaB. We conclude that signals for IL-12/p40 gene transcription from MHC class II molecules follow activation of PKC and PKA, which in turn leads to the activation and translocation of NF-kappaB to the nucleus. Our study suggests that superantigens are capable of influencing the nature of the immune response by regulating cytokine production. Induction of IL-12 production by superantigens may therefore play a role in the regulation of Th 1-mediated immune response and autoimmune disease.
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Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, Nashville, Tennessee 37212, USA.
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D000818:Animals; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011940:Receptor Aggregation; D015398:Signal Transduction; D018089:Superantigens / Q000276:immunology*; D015854:Up-Regulation
D000949:Histocompatibility Antigens Class II; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018089:Superantigens; D018664:Interleukin-12; D004247:DNA; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C