An analysis of the function and expression of D6 on lymphatic endothelial cells

McKimmie, C.S. et al. (2013) An analysis of the function and expression of D6 on lymphatic endothelial cells. Blood, 121(18), pp. 3768-3777. (doi: 10.1182/blood-2012-04-425314)

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Abstract

The mechanisms by which CCR7 ligands are selectively presented on lymphatic endothelium in the presence of inflammatory chemokines are poorly understood. The chemokine-scavenging receptor D6 is expressed on lymphatic endothelial cells (LEC) and contributes to selective presentation of CCR7 ligands by suppressing inflammatory chemokine binding to LEC surfaces. Here we show that, as well as preventing inappropriate inflammatory cell attachment to LECs, D6 is specifically involved in regulating the ability of LEC to discriminate between mature and immature DCs. D6 overexpression reduces immature DC adhesion to LECs, whilst D6 knockdown increases adhesion of immature DCs that displace mature DCs. LEC D6 expression is regulatable by growth factors, cytokines and tumor microenvironments. In particular IL-6 and IFNγ are potent inducers indicating a preferential role for D6 in inflamed contexts. Expression of the vIL-6 homologue from Kaposi's Sarcoma-Associated Herpesvirus (KSHV) is also sufficient to induce significant D6 up-regulation both in vitro and in vivo and KS, as well as Primary Effusion Lymphoma cells, demonstrate high levels of D6 expression. We therefore propose that D6, which is upregulated in both inflammatory and tumor contexts, is an essential regulator of inflammatory leukocyte interactions with LECs and is required for immature/mature DC discrimination by LECs.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lopez-Franco, Dr Oscar and Baker, Professor Andrew and Lee, Miss Kit and Nibbs, Professor Rob and Le Brocq, Dr Michelle and Singh, Mr Mark and McKimmie, Dr Clive and Graham, Professor Gerard
Authors: McKimmie, C.S., Singh, M.D., Hewit, K., Lopez-Franco, O., Le Brocq, M., Rose-John, S., Lee, K.M., Baker, A.H., Wheat, R., Blackbourn, D.J., Nibbs, R.J.B., and Graham, G.J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:11 March 2013

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