TGF or TNF Time series in ARPE19

Aberrant epithelial-mesenchymal transition (EMT) is involved inpathological processes including fibrotic disorders and cancer invasion and metastasis. Alterations of the cell-extracellular matrix(ECM) interaction also contribute to those pathological settings.However, the functional interplay between EMT and cell-ECMinteraction is poorly understood. Here, we show that tumor necrosis factor (TNF)-, a potent mediator of inflammation, inducesEMT-associated fibrosis in retinal pigment epithelial cells, and that this is regulated by hyaluronan (HA)-CD44-Moesin interaction. TNF- elicits both HA synthesis and Moesin phosphorylation through protein kinase C activation, promoting binding of CD44 to the newly synthesized HA. The HA-CD44-Moesin interaction leads to cell-cell dissociation through actin remodeling and increased cellular motility associated with mesenchymal phenotype. Furthermore, weestablished an in vivo model of TNF--induced fibrosis in the mouse eye, and the ocular fibrosis was completely suppressed in CD44-null mice. Therefore, HA production and its interaction with CD44 plays essential role in TNF--induced-EMT, and the interference of the complex formation can be a new strategy for the fibrotic disorders.

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