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The hyaluronan receptor LYVE-1 is selectively expressed in the endothelium of lymphatic capillaries, where it has been proposed to function in hyaluronan clearance and hyaluronan-mediated leukocyte adhesion. However, recent studies suggest that hyaluronan homeostasis is unperturbed in LYVE-1(-/-) mice and that lymphatic adhesion/transmigration may be largely mediated by ICAM-1 and VCAM-1 rather than LYVE-1. Here we have explored the possibility that LYVE-1 functions during inflammation and report that the receptor is down-regulated by pro-inflammatory cytokines. Using cultured primary lymphatic endothelial cells, we show that surface expression of LYVE-1 is rapidly and reversibly lost after exposure to tumor necrosis factor-alpha (TNFalpha) and TNFbeta via internalization and degradation of the receptor in lysosomes, coupled with a shutdown in gene expression. Curiously, internalization does not result in significant uptake of hyaluronan, a process that is largely insensitive to the novel LYVE-1 adhesion blocking monoclonal antibody 3A, and proceeds almost equally in resting and inflammation-activated lymphatic endothelial cells. Finally, we show that TNF can induce down-modulation of LYVE-1 in ex vivo murine dermal tissue explants and present evidence that the process occurs in vivo, in the context of murine allergen-induced skin inflammation. These findings suggest that LYVE-1 can function independently of hyaluronan and have implications for the use of LYVE-1 as a histological marker for lymphangiogenesis in human pathology.

Original publication

DOI

10.1074/jbc.M702889200

Type

Journal article

Journal

J Biol Chem

Publication Date

16/11/2007

Volume

282

Pages

33671 - 33680

Keywords

Allergens, Animals, Cell Adhesion, Gene Expression Regulation, Glycoproteins, Humans, Hyaluronic Acid, Inflammation, Leukocytes, Lymphangiogenesis, Lymphatic System, Lysosomes, Male, Membrane Transport Proteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Vascular Cell Adhesion Molecule-1, Vesicular Transport Proteins