title: The pro-fibrotic properties of transforming growth factor on human fibroblasts are counteracted by caffeic acid by inhibiting myofibroblast formation and collagen synthesis.
abstract: Fibrosis is a chronic disorder affecting many organs. A universal process in fibrosis is the formation of myofibroblasts and the subsequent collagen deposition by these cells. Transforming growth factor beta1 (TGFβ1) plays a major role in the formation of myofibroblasts, e.g. by activating fibroblasts. Currently, no treatments are available to circumvent fibrosis. Caffeic acid phenethyl ester (CAPE) shows a broad spectrum of biological activities, including anti-fibrotic properties in vivo in mice and rats. However, little is known about the direct effects of CAPE on fibroblasts. We have tested whether CAPE is able to suppress myofibroblast formation and collagen formation of human dermal and lung fibroblasts exposed to TGFβ1, and found that this was indeed the case. In fact, the formation of myofibroblasts by TGFβ1 and subsequent collagen formation was completely abolished by CAPE. The same was observed for fibronectin and tenascin C. The lack of myofibroblast formation is likely due to the suppression of GLI1 and GLI2 expression by CAPE because of diminished nuclear SMAD2/3 levels. Post-treatment with CAPE after myofibroblast formation even resulted in a partial reversal of myofibroblasts into fibroblasts and/or reduction in collagen formation. Major discrepancies were seen between mRNA levels of collagen type I and cells stained positive for collagen, underlining the need for protein data in fibrosis studies to make reliable conclusions.
authors.affiliation: Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Masum M
authors.initials: MM
authors.lastname: Mia
authors.affiliation: Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. R.A.Bank@umcg.nl.
authors.forename: Ruud A
authors.initials: RA
authors.lastname: Bank
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D002109:Caffeic Acids / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D019063:Tenascin / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D002109:Caffeic Acids; D024042:Collagen Type I; D005353:Fibronectins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D051785:Smad Proteins; D019063:Tenascin; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C051615:transgelin; C479138:PLOD2 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: Caffeic acid; Collagen; Fibrosis; Lysyl hydroxylase; Myofibroblasts