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J. Biol. Chem., Vol. 282, Issue 46, 33671-33680, November 16, 2007

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Inflammation-induced Uptake and Degradation of the Lymphatic Endothelial Hyaluronan Receptor LYVE-1^*

From the Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom

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- (TNF) and TNF 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.

Received for publication, April 4, 2007 , and in revised form, September 10, 2007.

^* This work was supported by generous funding from the UK Medical Research Council (MRC Human Immunology Unit) and by Project Grant AICR 00-311 from the Association for International Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1, showing comparison of the surface phenotypes of HDLEC derived by outgrowth from HMVEC and by LYVE-1 immunoselection, and Fig. S2, showing the time course for loss of LYVE-1 from lymphatic vessels in oxazolone-treated mouse ear dermis.

This article was selected as a Paper of the Week.

¹ Present address: Radiobiology Research Institute, Churchill Hospital, Oxford OX3 7LJ UK.

² To whom correspondence should be addressed. Tel.: 44-1865-222313; Fax: 44-1865-222502; E-mail: djackson{at}hammer.imm.ox.ac.uk.

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