Format

Send to

Choose Destination
Biochem Biophys Res Commun. 2018 Jan 1;495(1):801-806. doi: 10.1016/j.bbrc.2017.11.067. Epub 2017 Nov 11.

Endothelial Robo4 regulates IL-6 production by endothelial cells and monocytes via a crosstalk mechanism in inflammation.

Author information

1
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
2
The Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Electronic address: waird@bidmc.harvard.edu.
3
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan. Electronic address: okadabos@phs.osaka-u.ac.jp.

Abstract

Roundabout4 (Robo4) is an endothelial cell-specific receptor that stabilizes vasculature in pathological angiogenesis. Previous studies have shown that Robo4 is a potential therapeutic target for inflammatory diseases, but its precise roles in inflammation remain unclear. To investigate physiological Robo4 functions in inflammation, we performed a loss-of-function study in vitro and in vivo using lipopolysaccharide (LPS)-induced endotoxemia models. Subcutaneous injection of LPS into Robo4-knockout mice reduced circulating IL-6 levels. siRNA-mediated Robo4 knockdown suppressed IL-6 production induced by LPS, IL-1β, and TNFα, in human umbilical vein endothelial cells (HUVECs). Coculture experiments with HUVECs and a monocytic cell line, U937 cells, demonstrated that Robo4 knockdown suppresses IL-6 production by both endothelial cells and U937 cells. Further coculture experiments demonstrated that Robo4 knockdown inhibited a novel IL-6 amplification mechanism mediated by crosstalk between endothelial cells and U937 cells via direct interactions and two mediators, GM-CSF and IL-1β. Taken together, we demonstrated novel Robo4 functions in inflammation, i.e., it promotes IL-6 production by endothelial cells and immune cells via crosstalk.

KEYWORDS:

Endothelial cell; GM-CSF; IL-6; Inflammation; Monocyte; Robo4

PMID:
29137978
DOI:
10.1016/j.bbrc.2017.11.067
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center