Abstract
Aberrant epithelial-mesenchymal transition (EMT) is involved in development of fibrotic disorders and cancer invasion. Alterations of cell-extracellular matrix interaction also contribute to those pathological conditions. However, the functional interplay between EMT and cell-extracellular matrix interactions remains poorly understood. We now show that the inflammatory mediator tumor necrosis factor-alpha (TNF-alpha) induces the formation of fibrotic foci by cultured retinal pigment epithelial cells through activation of transforming growth factor-beta (TGF-beta) signaling in a manner dependent on hyaluronan-CD44-moesin interaction. TNF-alpha promoted CD44 expression and moesin phosphorylation by protein kinase C, leading to the pericellular interaction of hyaluronan and CD44. Formation of the hyaluronan-CD44-moesin complex resulted in both cell-cell dissociation and increased cellular motility through actin remodeling. Furthermore, this complex was found to be associated with TGF-beta receptor II and clathrin at actin microdomains, leading to activation of TGF-beta signaling. We established an in vivo model of TNF-alpha-induced fibrosis in the mouse eye, and such ocular fibrosis was attenuated in CD44-null mice. The production of hyaluronan and its interaction with CD44, thus, play an essential role in TNF-alpha-induced EMT and are potential therapeutic targets in fibrotic disorders.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cluster Analysis
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Epithelium / drug effects
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Epithelium / pathology
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Fibrosis
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Gene Expression Profiling
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism*
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Hyaluronic Acid / metabolism*
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Immunoblotting
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Mesoderm / drug effects
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Mesoderm / pathology
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Mice
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Mice, Knockout
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism*
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Models, Biological
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Oligonucleotide Array Sequence Analysis
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Retinal Pigment Epithelium / drug effects
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Retinal Pigment Epithelium / metabolism
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Retinal Pigment Epithelium / pathology
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Tissue Culture Techniques
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Transforming Growth Factor beta2 / genetics
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Transforming Growth Factor beta2 / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Hyaluronan Receptors
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Microfilament Proteins
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta2
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Tumor Necrosis Factor-alpha
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moesin
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Hyaluronic Acid
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II