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

Clive S McKimmie, Mark D Singh, Kay Hewit, Oscar Lopez-Franco, Michelle Le Brocq, Stefan Rose-John, Kit Ming Lee, Andrew H Baker, Rachel Wheat, David J Blackbourn, Robert J B Nibbs, Gerard J Graham

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanisms by which CC chemokine receptor (CCR)7 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. 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 dendritic cells (DCs). D6 overexpression reduces immature DC (iDC) adhesion to LECs, whereas D6 knockdown increases adhesion of iDCs that displace mature DCs. LEC D6 expression is regulated by growth factors, cytokines, and tumor microenvironments. In particular, interleukin-6 and interferon-γ are potent inducers, indicating a preferential role for D6 in inflamed contexts. Expression of the viral interleukin-6 homolog from Kaposi sarcoma-associated herpesvirus is also sufficient to induce significant D6 upregulation both in vitro and in vivo, and Kaposi sarcoma and 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.

Original languageEnglish
Pages (from-to)3768-77
Number of pages10
JournalBlood
Volume121
Issue number18
DOIs
Publication statusPublished - 2 May 2013

Keywords

  • Animals
  • CHO Cells
  • Cell Communication
  • Cell Differentiation
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Dendritic Cells
  • Endothelial Cells
  • HEK293 Cells
  • Humans
  • Inflammation
  • Neoplasms
  • Receptors, CCR10
  • Transfection

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