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Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Enhances Collagen Production by Human Lung Fibroblasts

Research Service, Veterans Affairs Maryland Health Care System and Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

Address correspondence to: Vladimir V. Yurovsky, University of Maryland School of Medicine, MSTF Room 8-19, 10 South Pine Street, Baltimore, MD 21201. E-mail: vyurovsk{at}umaryland.edu

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL/APO-2L) is a member of the tumor necrosis factor family that induces apoptosis in a variety of transformed cell lines and in normal human hepatocytes and brain cells. Soluble TRAIL at high concentrations was found to induce apoptotic death in normal human lung fibroblasts, whereas at low concentrations it was found to stimulate collagen production by these cells. Collagen 2(I) mRNA expression was assessed by semiquantitative reverse transcriptase/polymerase chain reaction; total soluble collagen was measured in culture supernatants by the Sircol assay. Both 2(I) collagen mRNA level and total soluble collagen secretion were increased upon TRAIL stimulation, with peak response (> 4-fold increase in mRNA level) at 1 ng/ml TRAIL. Analysis of the transcriptional response in TRAIL-stimulated fibroblasts, using DNA microarray hybridization, revealed an augmented expression of a number of genes involved in tissue remodeling, including those related to the transforming growth factor-ß (TGF-ß) pathway. DNA microarray results for the increase in TGF-ß1 mRNA level were confirmed by Northern blot analysis and by measurements of total active TGF-ß1 in culture supernatants. In addition, pan-specific TGF-ß antibody was shown to inhibit TRAIL-stimulated collagen mRNA and protein expression. These data suggest that TRAIL can enhance extracellular matrix synthesis in fibroblasts by triggering TGF-ß production that acts in an autocrine manner.

Abbreviations: fluorescein isothiocyanate, FITC • c-Jun N-terminal kinase, JNK • glyceraldehyde-3-phosphate dehydrogenase, GAPDH • nuclear factor B, NF-B • polymerase chain reaction, PCR • transforming growth factor-ß, TGF-ß • tumor necrosis factor–related apoptosis-inducing ligand, TRAIL

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