Aberrant production of IL-12 by macrophages from several autoimmune-prone mouse strains is characterized by intrinsic and unique patterns of NF-kappa B expression and binding to the IL-12 p40 promoter.
Intrinsic defects in macrophage (M(phi)) cytokine production characterize many autoimmune-prone mouse strains. Aberrant levels of IL-12, for example, are produced by M(phi) isolated from young mice prone to lupus (MRL and NZB/W) and diabetes (nonobese diabetic (NOD)) well before the appearance of disease signs. Evaluation of the possible mechanism(s) underlying the abnormal regulation of IL-12 in these strains revealed novel patterns of Rel family protein binding to the unique p40 NF-kappaB site in the IL-12 p40 promoter, whereas binding patterns to Ets and CCAAT enhancer binding protein/beta sites were normal. In particular, the heightened production of IL-12 by NOD M(phi) is associated with elevated levels of the trans-activating p50/c-Rel (p65) complex compared with the nonfunctional p50/p50 dimer. Conversely, the dramatically impaired production of IL-12 by both NZB/W and MRL/+ M(phi) is associated with a predominance of p50/p50 and reduced p50/c-Rel(p65) binding. Mechanistically, the unique pattern seen in the lupus strains reflects elevated p50 and reduced c-Rel nuclear protein levels. In NOD extracts, the level of c-Rel is elevated compared with that in lupus strains, but not when compared with that in normal A/J. However, the extent of c-Rel tyrosine phosphorylation noted in NOD extracts is more than double that seen in any other strain. Levels of p65 were similar in all strains tested. These findings reveal that a common mechanism, involving dysregulation of c-Rel and p50, may be used to determine the aberrant IL-12 levels that have the potential to predispose specific mouse strains to systemic or organ-specific autoimmunity.
Liu
Jiajian
J
Arthritis Section, Department of Medicine, Boston University Medical Center, Boston MA 02118, USA.
Beller
David
D
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002457:Cell Extracts / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D019281:Dimerization; D020022:Genetic Predisposition to Disease; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology; 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 / Q000096:biosynthesis* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D021122:Protein Subunits; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014443:Tyrosine / Q000378:metabolism
D002457:Cell Extracts; D004268:DNA-Binding Proteins; D053762:Interleukin-12 Subunit p40; D016328:NF-kappa B; D021122:Protein Subunits; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; D018664:Interleukin-12; D014443:Tyrosine