title: Distinct pathways for NF-kappa B regulation are associated with aberrant macrophage IL-12 production in lupus- and diabetes-prone mouse strains.
abstract: One characteristic of mice prone to a variety of autoimmune diseases is the aberrant regulation of cytokine production by macrophages (Mphi), noted in cells isolated well before the onset of disease. Strikingly, the pattern of IL-12 dysregulation, in particular, is consistent with the nature of the autoimmune disease that will develop in each strain, i.e., elevated in mice prone to Th1-mediated organ-specific disease (nonobese diabetic (NOD) and SJL mice) and reduced in lupus-prone strains (MRL/+ and NZB/W). Mechanistically, the abnormal regulation of IL-12 in these strains was found to be strictly associated with novel patterns of Rel binding in vitro to the unique NF-kappaB site in the IL-12 p40 promoter. In this study, we report several new findings related to these Rel-kappaB interactions. Evaluation of the p40 NF-kappaB site in vivo, assessed by chromatin immunoprecipitation, revealed Rel usage patterns similar to those found in vitro using EMSA, with preferential association of the p40 kappaB site with c-Rel in NOD Mphi but with p50 in NZB/W Mphi. Moreover, blocking c-Rel in primary Mphi, using short interfering RNA, selectively blocked IL-12 production and normalized the minimal, residual IL-12 levels. Nuclear extracts from NOD Mphi were characterized by c-Rel hyperphosphorylation, and dephosphorylation of nuclear proteins completely blocked binding to the kappaB site. In contrast, elevated IkappaB appears to be a likely mechanism accounting for the reduced nuclear c-Rel levels noted in NZB/W Mphi. Alterations in NF-kappaB metabolism thus appear to define a pathway regulating intrinsic IL-12 defects in both diabetes- and lupus-prone strains.
authors.affiliation: Arthritis Section, Evans Department of Medicine and Clinical Research, Boston University Medical Campus, Boston, MA 02118, USA.
authors.forename: Jiajian
authors.initials: J
authors.lastname: Liu
authors.forename: David I
authors.initials: DI
authors.lastname: Beller
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D020672:I-kappa B Proteins / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D008814:Mice, Inbred NZB; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D021122:Protein Subunits / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D020569:Proto-Oncogene Proteins c-rel / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051996:Transcription Factor RelA; D015854:Up-Regulation / Q000276:immunology
chemical_list: C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D053762:Interleukin-12 Subunit p40; D016328:NF-kappa B; C491366:Nfkbie protein, mouse; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA; D018664:Interleukin-12