5Z-7-Oxozeanol Inhibits the Effects of TGFβ1 on Human Gingival Fibroblasts.
Transforming growth factor (TGF)β acts on fibroblasts to promote the production and remodeling of extracellular matrix (ECM). In adult humans, excessive action of TGFβ is associated with fibrotic disease and fibroproliferative conditions, including gingival hyperplasia. Understanding how the TGFβ1 signals in fibroblasts is therefore likely to result in valuable insights into the fundamental mechanisms underlying fibroproliferative disorders. Previously, we used the TAK1 inhibitor (5Z)-7-Oxozeaenol to show that, in dermal fibroblasts, the non-canonical TAK1 pathway mediates the ability of TGFβ1 to induce genes promoting tissue remodeling and repair. However, the extent to which TAK1 mediates fibroproliferative responses in fibroblasts in response to TGFβ1 remains unclear. Herein, we show that, in gingival fibroblasts, (5Z)-7-Oxozeaenol blocks the ability of TGFβ1 to induce expression of the pro-fibrotic mediator CCN2 (connective tissue growth factor, CTGF) and type I collagen protein. Moreover, genome-wide expression profiling revealed that, in gingival fibroblasts, (5Z)-7-Oxozeaenol reduces the ability of TGFβ1 to induce mRNA expression of essentially all TGFβ1-responsive genes (139/147), including those involved with a hyperproliferative response. Results from microarray analysis were confirmed using real time polymerase chain reaction analysis and a functional cell proliferation assay. Our results are consistent with the hypothesis that TAK1 inhibitors might be useful in treating fibroproliferative disorders, including that in the oral cavity.
Department of Physiology and Pharmacology, The University of Western Ontario, Schulich School of Medicine and Dentistry, London, Ontario, Canada, N6A 5C1.
Hanna
H
Kuk
Department of Physiology and Pharmacology, The University of Western Ontario, Schulich School of Medicine and Dentistry, London, Ontario, Canada, N6A 5C1.
James
J
Hutchenreuther
Department of Dentistry, The University of Western Ontario, Schulich School of Medicine and Dentistry, London, Ontario, Canada, N6A 5C1.
Hannah
H
Murphy-Marshman
London Regional Genomics Centre, Robarts Research Institute, London, ON, Canada, N6A 5B7.
David
D
Carter
Department of Physiology and Pharmacology, The University of Western Ontario, Schulich School of Medicine and Dentistry, London, Ontario, Canada, N6A 5C1; Department of Dentistry, The University of Western Ontario, Schulich School of Medicine and Dentistry, London, Ontario, Canada, N6A 5C1.
Andrew
A
Leask
D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005881:Gingiva / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D012118:Resorcinols / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7; D015025:Zearalenone / Q000008:administration & dosage
D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D007783:Lactones; D020930:MAP Kinase Kinase Kinases; D012118:Resorcinols; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D015025:Zearalenone; C526317:CCN2 protein, human; C508960:TGFB1 protein, human