5Z-7-Oxozeanol Inhibits the Effects of TGF[beta]1 on Human Gingival Fibroblasts

• Published in: PloS one Vol. 10; no. 4
• Main Authors: Kuk, Hanna, Hutchenreuther, James, Murphy-Marshman, Hannah, Carter, David, Leask, Andrew
• Format: Journal Article
• Language: English
• Published: Public Library of Science 30.04.2015
• Subjects: Analysis; Collagen; DNA microarrays; RNA; Transforming growth factors
• DOI: 10.1371/journal.pone.0123689
• ISSN: 1932-6203

Transforming growth factor (TGF)[beta] acts on fibroblasts to promote the production and remodeling of extracellular matrix (ECM). In adult humans, excessive action of TGF[beta] is associated with fibrotic disease and fibroproliferative conditions, including gingival hyperplasia. Understanding how the TGF[beta]1 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 TGF[beta]1 to induce genes promoting tissue remodeling and repair. However, the extent to which TAK1 mediates fibroproliferative responses in fibroblasts in response to TGF[beta]1 remains unclear. Herein, we show that, in gingival fibroblasts, (5Z)-7-Oxozeaenol blocks the ability of TGF[beta]1 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 TGF[beta]1 to induce mRNA expression of essentially all TGF[beta]1-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.