NF-kappa B p65 antagonizes IL-4 induction by c-maf in minimal change nephrotic syndrome.
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.
Valanciuté
Asta
A
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.
le Gouvello
Sabine
S
Solhonne
Brigitte
B
Pawlak
André
A
Grimbert
Philippe
P
Lyonnet
Luc
L
Hue
Sophie
S
Lang
Philippe
P
Remy
Philippe
P
Salomon
Rémy
R
Bensman
Albert
A
Guellaën
Georges
G
Sahali
Djillali
D
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
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