Gene expression profiling of pulmonary fibrosis identifies Twist1 as an antiapoptotic molecular "rectifier" of growth factor signaling.
Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into IPF pathogenesis, we performed gene expression profiling of IPF lungs. Twist1, a basic helix-loop-helix protein, was found among the most consistently and highly up-regulated genes and was expressed in nuclei of type II epithelial cells, macrophages, and fibroblasts in IPF lungs. We studied the function of Twist1 in fibroblasts further, because they are the major effector cells in this disease and persist despite an ambient proapoptotic environment. Twist1 was induced by the profibrotic growth factors (GFs) basic fibroblast growth factor, platelet-derived growth factor, and epidermal growth factor in primary rat lung fibroblasts (RLFs). Suppression of Twist1 expression resulted in decreased RLF accumulation due to increased apoptosis, whereas Twist1 overexpression protected RLFs against several apoptotic stimuli. Addition of platelet-derived growth factor in combination with other GFs led to an increase in proliferation. When Twist1 was depleted, GFs continued to act as mitogens but caused a marked increase in cell death. The increase in apoptosis under basal or growth factor-stimulated conditions was partly mediated by up-regulation of the proapoptotic Bcl-2 family members, Bim and PUMA. These findings indicate that Twist1 promotes survival and accumulation of fibroblasts by shaping their responsiveness to growth factor stimulation. We propose that Twist1 represents one of the factors that promotes pathogenic accumulation of fibroblasts in fibrotic lung disease.
Bridges
Robert S
RS
Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Kass
Daniel
D
Loh
Katrina
K
Glackin
Carlota
C
Borczuk
Alain C
AC
Greenberg
Steven
S
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000096:biosynthesis / Q000235:genetics*
D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1