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TRAIL-mediated enhancement of collagen production by human lung fibroblasts

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that induces apoptosis in a variety of transformed cell lines and in normal human hepatocytes in vitro. The expression of TRAIL was found in CD8 T cells that had undergone oligoclonal expansion in the lungs of patients with systemic sclerosis (scleroderma) and were able to stimulate collagen production in lung fibroblasts in vitro. Among the family members, TRAIL displays highest homology to CD95 ligand, a receptor of which may not only mediate apoptosis of T cells, but also mediate the proliferation of normal human fibroblasts. Considering structural and functional similarities between TRAIL and CD95 ligand, we examined the effects of soluble TRAIL on normal human lung fibroblasts. Collagen α2(I) mRNA expression was assessed by real-time RT-PCR, with ribosomal protein S9 as an internal standard. Total soluble collagen was measured in culture supernatants using the Sircol Biocolor Assay. Both normalized α2(I) collagen mRNA expression and total soluble collagen secretion were increased upon TRAIL stimulation, with peak response (>5-fold increase) at 10 ng/ml TRAIL. DNA microarray hybridization revealed 78 genes involved in signal transduction, DNA transcription, and tissue remodeling, whose expression level increased, and 8 genes whose expression level decreased >2.5-fold in comparison with quiescent fibroblasts. Augmented expression of a number of genes involved in the TGFβ pathway suggested that TRAIL might induce TGFβ-mediated autocrine and/or paracrine stimulation of fibroblasts. This was confirmed by the ability of anti-TGFβ antibody to inhibit the effects of TRAIL on collagen production by fibroblasts. DNA mobility shift assay also revealed TRAIL-induced increase in protein binding to the collagen promoter that was substantially inhibited by consensus oligonucleotide for Smad3/4, mediators of TGFβ signaling. These data suggest that TRAIL can enhance extracellular matrix synthesis in fibroblasts by triggering TGFβ production, which acts in autocrine manner.

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Yurovsky, V. TRAIL-mediated enhancement of collagen production by human lung fibroblasts. Arthritis Res Ther 4 (Suppl 1), 54 (2002).

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