title: Tumor necrosis factor-alpha regulates transforming growth factor-beta-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction.
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.
authors: From the Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582; the Department of Ophthalmology and Visual Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556.
authors: Eri
authors: E
authors: Takahashi
authors: From the Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582; the Japan Science and Technology Agency, CREST, Tokyo 102-0075.
authors: Osamu
authors: O
authors: Nagano
authors: From the Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582.
authors: Takatsugu
authors: T
authors: Ishimoto
authors: From the Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582.
authors: Toshifumi
authors: T
authors: Yae
authors: the Department of Biomedical Research and Development, Link Genomics Inc., Tokyo 103-0024, and.
authors: Yoshimi
authors: Y
authors: Suzuki
authors: the Department of Biomedical Research and Development, Link Genomics Inc., Tokyo 103-0024, and.
authors: Takeshi
authors: T
authors: Shinoda
authors: the Department of Biomedical Research and Development, Link Genomics Inc., Tokyo 103-0024, and.
authors: Satoshi
authors: S
authors: Nakamura
authors: the Department of Biomedical Research and Development, Link Genomics Inc., Tokyo 103-0024, and.
authors: Shinichiro
authors: S
authors: Niwa
authors: the Laboratory of Medical Genomics, Department of Human Genome Research, Kazusa DNA Research Institute, Chiba 292-0818, Japan.
authors: Shun
authors: S
authors: Ikeda
authors: the Laboratory of Medical Genomics, Department of Human Genome Research, Kazusa DNA Research Institute, Chiba 292-0818, Japan.
authors: Hisashi
authors: H
authors: Koga
authors: the Department of Ophthalmology and Visual Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556.
authors: Hidenobu
authors: H
authors: Tanihara
authors: From the Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582; the Japan Science and Technology Agency, CREST, Tokyo 102-0075. Electronic address: hsaya@a5.keio.jp.
authors: Hideyuki
authors: H
authors: Saya
mesh_terms: D000818:Animals; D002460:Cell Line; D016000:Cluster Analysis; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D020869:Gene Expression Profiling; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D015151:Immunoblotting; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018960:Hyaluronan Receptors; D008840:Microfilament Proteins; D018125:Receptors, Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D014409:Tumor Necrosis Factor-alpha; C071058:moesin; D006820:Hyaluronic Acid; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II