Global expression profiling of fibroblast responses to transforming growth factor-beta1 reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching.
Transforming growth factor-beta1 (TGF-beta1) plays a central role in promoting extracellular matrix protein deposition by promoting the transformation of fibroblasts to myofibroblasts. To gain new insights into the transcriptional programs involved, we profiled human fetal lung fibroblast global gene expression in response to TGF-beta1 up to 24 hours using oligonucleotide microarrays. In this report, we present data for 146 genes that were up-regulated at least twofold at two time points. These genes group into several major functional categories, including genes involved in cytoskeletal reorganization (n = 30), matrix formation (n = 25), metabolism and protein biosynthesis (n = 27), cell signaling (n = 21), proliferation and survival (n = 13), gene transcription (n = 9), and of uncertain function (n = 21). For 80 of these genes, this is the first report that they are TGF-beta1-responsive. The early induction of two members of the inhibitor of differentiation (ID) family of transcriptional regulators, ID1 and ID3, was followed by the up-regulation of a number of genes that are usually expressed by highly differentiated smooth muscle cells, including smooth muscle myosin heavy chain, basic calponin, and smoothelin. These findings were confirmed at the protein level for primary adult lung fibroblasts. ID1 further behaved like a typical immediate-early gene and, unlike ID3, was expressed and induced at the protein level. Immunohistochemical analysis showed that ID1 was highly expressed by (myo)fibroblasts within fibrotic foci in experimentally induced pulmonary fibrosis. ID1 acts as a dominant-negative antagonist of basic helix-loop-helix transcription factors that drive cell lineage commitment and differentiation. These findings have important implications for our understanding of fibroblast transcriptional programming in response to TGF-beta1 during development, oncogenesis, tissue repair, and fibrosis.
Chambers
Rachel C
RC
Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, Royal Free and University College Medical School, University College London, Rayne Institute, London, United Kingdom. r.chambers@ucl.ac.uk
Leoni
Patricia
P
Kaminski
Naftali
N
Laurent
Geoffrey J
GJ
Heller
Renu A
RA
D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D005333:Fetus; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D020869:Gene Expression Profiling; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007150:Immunohistochemistry; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D008168:Lung; D009130:Muscle, Smooth / Q000166:cytology / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C508960:TGFB1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C075640:ID3 protein, human