Regular article
Cell injury, repair, aging, and apoptosis
The Critical Role of TAK1 in Accentuated Epithelial to Mesenchymal Transition in Obliterative Bronchiolitis after Lung Transplantation

https://doi.org/10.1016/j.ajpath.2012.02.022Get rights and content
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Therapies to limit or reverse fibrosis have proven unsuccessful, highlighting the need for a greater understanding of basic mechanisms that drive fibrosis and, in particular, the link between fibrosis and inflammation. It has been shown that pro-fibrotic transforming growth factor β1 (TGF-β1)–driven epithelial-to-mesenchymal transition (EMT) can be accentuated by tumor necrosis factor α (TNF-α). TGF-β–activated kinase 1 (TAK1) is activated by both TGF-β1 and TNF-α, activating both nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase signaling pathways. In this study, we evaluated the potential for TAK1 to modulate the synergistic effect between TGF-β1 and TNF-α in driving EMT. Co-stimulation with TGF-β1 and TNF-α induced an accentuated and extended phosphorylation of TAK1 compared to either alone. TAK1 signaled downstream via nuclear factor kappa-light-chain-enhancer of activated B cells, and Jun N-terminal kinase-2, but independent of Jun N-terminal kinase-1, extracellular signal-regulated kinase-1/2, or p38 mitogen-activated protein kinase signaling to drive EMT in bronchial epithelial cells. Blocking either TAK1 or Jun N-terminal kinase-2 inhibited EMT. TAK1 phosphorylation was increased in the airway epithelium of patients with fibrotic airway disease. These data identify factors leading to and affected by accentuated and extended TAK1 phosphorylations potential novel therapeutic targets in inflammation-driven fibrotic diseases.

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Supported by a research grant from the Medical Research Council UK (G0700861); a GlaxoSmithKline clinical fellowship award (A.J.F.); the Wellcome Trust (WT086755MA to D.A.M.); and a Marie Curie fellowship award (L.A.B.).

Supplemental material for this article can be found on http://ajp.amjpathol.org or at http://dx.doi.org/10.1016/j.ajpath.2012.02.022.