title: NF-kappa B p65 antagonizes IL-4 induction by c-maf in minimal change nephrotic syndrome.
abstract: Mechanisms underlying the pathophysiology of minimal change nephrotic syndrome (MCNS), the most frequent of glomerular diseases in children, remain elusive, although recent arguments suggest that T cell dysfunction may be involved in the pathogenesis of this disease. Recently, we reported that activated T cells of these patients display a down-regulation of IL-12R beta2 chain, suggesting an early commitment toward Th2 phenotype. In this study, we show that the short form of the proto-oncogene c-maf, a known activator of the IL-4 gene, is highly induced in MCNS T cells during relapse, where it translocates to the nuclear compartment and binds to the DNA responsive element. Unexpectedly, the nuclear localization of c-maf did not promote the IL-4 gene transcription in relapse. Using several approaches, we show in this study that RelA blunts IL-4 induction in T cells during the relapse in these patients. We demonstrate that the ex vivo inhibition of proteasome activity in T cells from relapse, which blocks NF-kappaB activity, strongly increases the IL-4 mRNA levels. Overexpression of c-maf in T cells induces a high level of IL-4 promoter-driven luciferase activity. In contrast, coexpression of c-maf with NF-kappaB RelA/p50, or RelA, but not p50, inhibits the c-maf-dependent IL-4 promoter activity. Finally, we demonstrated that, in T cell overexpressing RelA and c-maf, RelA expelled c-maf from its DNA binding site on IL-4 gene promoter, which results in active inhibition of IL-4 gene transcription. Altogether, these results suggest that the involvement of c-maf in Th2 commitment in MCNS operates through IL-4-independent mechanisms.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 581, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, 51 Avenue du Marechal de Lattre-de-Tassigny, 94010 Créteil, France.
authors.forename: Asta
authors.initials: A
authors.lastname: Valanciuté
authors.forename: Sabine
authors.initials: S
authors.lastname: le Gouvello
authors.forename: Brigitte
authors.initials: B
authors.lastname: Solhonne
authors.forename: André
authors.initials: A
authors.lastname: Pawlak
authors.forename: Philippe
authors.initials: P
authors.lastname: Grimbert
authors.forename: Luc
authors.initials: L
authors.lastname: Lyonnet
authors.forename: Sophie
authors.initials: S
authors.lastname: Hue
authors.forename: Philippe
authors.initials: P
authors.lastname: Lang
authors.forename: Philippe
authors.initials: P
authors.lastname: Remy
authors.forename: Rémy
authors.initials: R
authors.lastname: Salomon
authors.forename: Albert
authors.initials: A
authors.lastname: Bensman
authors.forename: Georges
authors.initials: G
authors.lastname: Guellaën
authors.forename: Djillali
authors.initials: D
authors.lastname: Sahali
mesh_terms: D000293:Adolescent; D000328:Adult; D001665:Binding Sites / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology*; D009402:Nephrosis, Lipoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D051257:Proto-Oncogene Proteins c-maf; D012333:RNA, Messenger / Q000096:biosynthesis; D012008:Recurrence; D051996:Transcription Factor RelA; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; C495607:MAF protein, human; C000715470:MAS1 protein, human; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D015847:Interleukin-4