Interleukin-7 and transforming growth factor-beta play counter-regulatory roles in protein kinase C-delta-dependent control of fibroblast collagen synthesis in pulmonary fibrosis.
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.
Zhang
Ling
L
Department of Pathology, David Geffen School of Medicine at UCLA and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90095, USA.
Keane
Michael P
MP
Zhu
Li X
LX
Sharma
Sherven
S
Rozengurt
Enrique
E
Strieter
Robert M
RM
Dubinett
Steven M
SM
Huang
Min
M
D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000737:chemistry / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
C439971:COL3A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D015851:Interleukin-7; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D013912:Threonine; D012694:Serine; D012313:RNA; D003094:Collagen; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta