Tumor necrosis factor-alpha regulates transforming growth factor-beta-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction.
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.
Takahashi
Eri
E
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.
Nagano
Osamu
O
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.
Ishimoto
Takatsugu
T
From the Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582.
Yae
Toshifumi
T
From the Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582.
Suzuki
Yoshimi
Y
the Department of Biomedical Research and Development, Link Genomics Inc., Tokyo 103-0024, and.
Shinoda
Takeshi
T
the Department of Biomedical Research and Development, Link Genomics Inc., Tokyo 103-0024, and.
Nakamura
Satoshi
S
the Department of Biomedical Research and Development, Link Genomics Inc., Tokyo 103-0024, and.
Niwa
Shinichiro
S
the Department of Biomedical Research and Development, Link Genomics Inc., Tokyo 103-0024, and.
Ikeda
Shun
S
the Laboratory of Medical Genomics, Department of Human Genome Research, Kazusa DNA Research Institute, Chiba 292-0818, Japan.
Koga
Hisashi
H
the Laboratory of Medical Genomics, Department of Human Genome Research, Kazusa DNA Research Institute, Chiba 292-0818, Japan.
Tanihara
Hidenobu
H
the Department of Ophthalmology and Visual Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556.
Saya
Hideyuki
H
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.
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*
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