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Molecular cross-talk between the TRAIL and TGF-β pathways in human lung fibroblasts
- VV Yurovsky1
© BioMed Central Ltd 2003
- Received: 14 January 2003
- Published: 24 February 2003
- Systemic Sclerosis
- Human Lung Fibroblast
- Collagen mRNA
- Soluble Collagen
- Extracellular Matrix Production
Tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) has been closely associated with regulation of the immune response and pathogenesis of autoimmune diseases. The expression of TRAIL was found in CD8 T cells that had undergone oligoclonal expansion in the lungs of patients with systemic sclerosis and were able to stimulate collagen production in lung fibroblasts. Soluble, multimerized TRAIL and normal human lung fibroblasts were used as a model of selective TRAIL influence on fibroblasts. TRAIL was found to increase both α2(I) collagen mRNA expression and total soluble collagen secretion, with peak response at 1 ng/ml TRAIL. DNA microarray analysis suggested that fibroblast response to TRAIL might be mediated by c-Jun N-terminal kinase (JNK). The increase in JNK1 expression and phosphorylation as well as phosphorylation of its specific substrate were confirmed by Western blotting. The treatment of fibroblasts with TRAIL also enhanced the expression of a number of genes involved in tissue remodeling, including those related to the transforming growth factor (TGF) beta pathway. The increase in TGF-β1 mRNA level was confirmed by Northern blotting and by measurements of active TGF-β1 in culture supernatants. In addition, antibody-mediated blocking of TGF-β was shown to abrogate TRAIL-induced collagen synthesis. These data suggest that TRAIL can enhance extracellular matrix production in fibroblasts by triggering expression of TGF-β, which acts in an autocrine manner. If this process continues uncontrolled, it may contribute to the development of fibrosis, particularly in the lungs of patients with systemic sclerosis.