Premium
Sublytic C5b‐9 induces IL‐6 and TGF‐β1 production by glomerular mesangial cells in rat Thy‐1 nephritis through p300‐mediated C/EBPβ acetylation
Author(s) -
Zhang Jing,
Li Yan,
Shan Kai,
Wang Lulu,
Qiu Wen,
Lu Yanlai,
Zhao Dan,
Zhu Ganqian,
He Fengxia,
Wang Yingwei
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-242693
Subject(s) - downregulation and upregulation , nephritis , transforming growth factor , chemistry , mesangial cell , endocrinology , kidney , medicine , microbiology and biotechnology , biology , gene , biochemistry
The increased production of interleukin 6 (IL‐6) and transforming growth factor β1 (TGF‐β1) by glomerular mesangial cells (GMCs) in rat Thy‐1 nephritis (Thy‐1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by sublytic C5b‐9 deposition, but the mechanism of IL‐6 and TGF‐β1 upregulation in rat GMCs triggered by sublytic C5b‐9 in this model has not been elucidated. In the present study, molecular biological methods, along with functional and histological studies, were performed. We found that sublytic C5b‐9 (here, <5% lactate dehydrogenase release from cells is regarded as a sublytic effect) could induce the production of IL‐6 and TGF‐β1 through upregulation of p300 and C/EBPβ expression in GMCs, which might contribute to renal Th17/IL‐17 production in Thy‐1N rats. In addition, CCAAT/enhancer‐binding protein (C/EBPβ)‐enhanced IL‐6 and TGF ‐β 1 promoter activity and p300‐mediated C/EBPβ acetylation were involved in upregulation of IL‐6 and TGF‐β1 expression in GMCs attacked by sublytic C5b‐9. In detail, the elements of C/EBPβ binding to rat IL‐6 and TGF ‐β 1 promoter and 3 acetylated sites of rat C/EBPβ protein were first revealed. Furthermore, silencing the p300 or C/EBPβ gene in rat kidney significantly reduced the production of IL‐6 and TGF‐β1 and renal lesions in Thy‐1N rats. Together, these data indicate that the mechanism of IL‐6 and TGF‐β1 production in renal tissue of Thy‐1N rats is associated with sublytic C5b‐9 upregulated p300 and p300‐mediated C/EBPβ acetylation as well as C/EBPβ‐activated IL‐6 and TGF‐β1 genes.—Zhang, J., Li, Y., Shan, K., Wang, L., Qiu, W., Lu, Y., Zhao, D., Zhu, G., He, F., Wang, Y. Sublytic C5b‐9 induces IL‐6 and TGF‐β1 production by glomerular mesangial cells in rat Thy‐1 nephritis through p300‐mediated C/EBPβ acetylation. FASEB J. 28, 1511–1525 (2014). www.fasebj.org