期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 279, 期 27, 页码 28315-28319出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.C400115200
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资金
- NCI NIH HHS [P50 CA 90388, R01 CA 085686] Funding Source: Medline
- NHLBI NIH HHS [P01 HL 03906, P50 HL 67665] Funding Source: Medline
Transforming growth factor-beta (TGF-beta) is a potent fibrogenic factor responsible for promoting synthesis of extracellular matrix. Interleukin-7 (IL-7) inhibits TGF-beta signaling by up-regulating Smad7, a major inhibitor of the Smad family. In a variety of cells, TGF-beta-mediated activation of target genes requires active protein kinase C-delta (PKC-delta) in addition to Smads (1). We determined the role of PKC-delta in the regulation of pulmonary fibroblast collagen synthesis in response to TGF-beta and IL-7 stimulation. Here we show that TGF-beta and IL-7 have opposing effects on PKC-delta; TGF-beta stimulates, while IL-7 inhibits, PKC-delta activity. IL-7 inhibits TGF-beta-induced PKC-delta phosphorylation at Ser-645 and Thr-505. Inhibition of PKC-delta with specific small inhibitory RNA restores TGF-beta-mediated induction of Smad7 and in parallel significantly reduces TGF-beta-mediated collagen synthesis. Thus, PKC-delta may play a critical role in the pathogenesis of pulmonary fibrosis and may serve as a molecular target for therapeutic intervention to suppress fibrosis.
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