1. Specific signals involved in the long-term maintenance of radiation-induced fibrogenic differentiation: a role for CCN2 and low concentration of TGF-beta1
- Author
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Bruce L. Riser, Valérie Haydont, Jocelyne Aigueperse, Marie-Catherine Vozenin-Brotons, Laboratoire de Radiopathologie et Thérapies Expérimentales, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), and Rosalind Franklin University of Medicine and Science
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cancer patient ,enzyme assay ,Physiology ,[SDV]Life Sciences [q-bio] ,RNA 18S ,recombinant transforming growth factor beta1 ,radiation exposure ,Radiation induced ,Smad Proteins ,SMAD ,cancer cell culture ,intestine obstruction ,fluorescence activated cell sorting ,low drug dose ,Pathogenesis ,0302 clinical medicine ,Smooth Muscle ,Fibrosis ,Rho kinase ,mesenchyme cell ,genetics ,Volume concentration ,Cells, Cultured ,0303 health sciences ,rho-Associated Kinases ,Cultured ,integumentary system ,messenger RNA ,adult ,pathogenesis ,article ,Long term maintenance ,Cell Differentiation ,Middle Aged ,Recombinant Proteins ,3. Good health ,Cell biology ,radiation enteropathy ,colon cancer ,priority journal ,030220 oncology & carcinogenesis ,Intercellular Signaling Peptides and Proteins ,radiation injury ,Signal Transduction ,Transcriptional Activation ,Colon ,enzymology ,Cells ,Myocytes, Smooth Muscle ,Biology ,Immediate-Early Proteins ,reverse transcription polymerase chain reaction ,Transforming Growth Factor beta1 ,03 medical and health sciences ,intestine resection ,transactivation ,Ileum ,medicine ,case report ,Humans ,signal peptide ,controlled study ,human ,immediate early protein ,Radiation Injuries ,Smad protein ,030304 developmental biology ,Aged ,cell culture ,Myocytes ,Radiotherapy ,human cell ,Mesenchymal stem cell ,Connective Tissue Growth Factor ,cell type ,nucleotide sequence ,Cell Biology ,Trans-Activation (Genetics) ,medicine.disease ,Enzyme Activation ,Intestinal Diseases ,Rho factor ,enteropathy ,smooth muscle fiber ,Immunology ,gene expression ,pathology ,metabolism ,recombinant protein ,Transforming growth factor - Abstract
The fibrogenic differentiation of resident mesenchymal cells is a key parameter in the pathogenesis of radiation fibrosis and is triggered by the profibrotic growth factors transforming growth factor (TGF)-β1 and CCN2. TGF-β1 is considered the primary inducer of fibrogenic differentiation and is thought to control its long-term maintenance, whereas CCN2 is considered secondary effector of TGF-β1. Yet, in long-term established fibrosis like that associated with delayed radiation enteropathy, in situ TGF-β1 deposition is low, whereas CCN2 expression is high. To explore this apparent paradox, cell response to increasing doses of TGF-β1 was investigated in cells modeling initiation and maintenance of fibrosis, i.e., normal and fibrosis-derived smooth muscle cells, respectively. Activation of cell-specific signaling pathways by low TGF-β1 doses was demonstrated with a main activation of the Rho/ROCK pathway in fibrosis-derived cells, whereas the Smad pathway was mainly activated in normal cells. This leads to subsequent and cell-specific regulation of the CCN2 gene. These results suggested a specific profibrotic role of CCN2 in fibrosis-initiated cells. Furthermore, the modulation of CCN2 expression by itself and the combination of TGF-β1 and CCN2 was investigated in fibrosis-derived cells. In fibrosis-initiated cells CCN2 triggered its autoinduction; furthermore, low concentration of TGF-β1-potentiated CCN2 autoinduction. Our findings showed a differential requirement and action of TGF-β1 in the fibrogenic response of normal vs. fibrosis-derived cells. This study defines a novel Rho/ROCK but Smad3-independent mode of TGF-β signaling that may operate during the chronic stages of fibrosis and provides evidence of both specific and combinatorial roles of low TGF-β1 dose and CCN2. Copyright © 2008 the American Physiological Society.
- Published
- 2008
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