Tumor necrosis factor-α regulates transforming growth factor-β-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction

Eri Takahashi, Osamu Nagano, Takatsugu Ishimoto, Toshifumi Yae, Yoshimi Suzuki, Takeshi Shinoda, Satoshi Nakamura, Shinichiro Niwa, Shun Ikeda, Hisashi Koga, Hidenobu Tanihara, Hideyuki Saya

Research output: Contribution to journalArticle

115 Citations (Scopus)

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.Wenow show that the inflammatory mediator tumor necrosis factor-α (TNF-α) induces the formation of fibrotic foci by cultured retinal pigment epithelial cells through activation of transforming growth factor-β (TGF-β) signaling in a manner dependent on hyaluronan-CD44-moesin interaction. TNF-α 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-β receptor II and clathrin at actin microdomains, leading to activation of TGF-β signaling. We established an in vivo model of TNF-α-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-α-induced EMT and are potential therapeutic targets in fibrotic disorders.

Original languageEnglish
Pages (from-to)4060-4073
Number of pages14
JournalJournal of Biological Chemistry
Volume285
Issue number6
DOIs
Publication statusPublished - 2010 Feb 5

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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