Interleukin-6 promotes destabilized angiogenesis by modulating angiopoietin expression in rheumatoid arthritis.

Abstract

OBJECTIVE:

To examine whether IL-6 promotes angiogenesis by modulating angiopoietin (Ang) expression in RA.

METHODS:

Synovial fibroblasts derived from RA patients (RASFs) and human umbilical vein endothelial cells (HUVECs) were co-cultured for 6 days with or without recombinant IL-6, VEGF or Ang-1. HUVECs were stained with anti-CD31 antibody and their growth was determined by quantifying the CD31-positive area. SFs were collected from RA (n = 25) and OA (n = 7) patients.

RESULTS:

In the co-culture system, IL-6 and VEGF significantly enhanced HUVEC growth to a similar extent. However, the morphology of proliferating cells was distinct between IL-6- and VEGF-stimulated HUVEC. HUVEC stimulated with IL-6 exhibited small, loose clusters surrounded by dispersed single cells, suggesting destabilized angiogenesis by IL-6. In the supernatants, IL-6 up-regulated VEGF compared with controls and Ang-2, while it down-regulated Ang-1. In contrast, down-regulation of Ang-1 was not observed with VEGF stimulation. Consistent with the destabilized morphology, stimulation with IL-6 decreased cell surface expression of vascular endothelial cadherin (VE-cadherin) on HUVEC, presumably by inducing internalization. Interestingly, adding recombinant Ang-1 partially inhibited IL-6-induced morphological changes in HUVEC including a destabilized morphology with small, loose clusters and internalization of VE-cadherin. In SFs from RA patients, VEGF was negatively correlated with Ang-1 (r = -0.559, P=0.004).

CONCLUSION:

IL-6 not only enhances VEGF expression but also inhibits Ang-1 signalling by directly down-regulating Ang-1 expression and up-regulating Ang-2, an antagonist of Ang-1. These synergistic effects may play a critical role in destabilized angiogenesis in RA.

• Authors: Ken Kayakabe, Takashi Kuroiwa, Noriyuki Sakurai, Hidekazu Ikeuchi, Anastasie Tshilela Kadiombo, Toru Sakairi, Takayuki Matsumoto, Akito Maeshima, Keiju Hiromura, Yoshihisa Nojima
• Journal: Rheumatology (Oxford, England) (Rheumatology (Oxford)) Vol. 51 Issue 9 Pg. 1571-9 (Sep 2012) ISSN: 1462-0332 [Electronic] England
• PMID: 22596210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ANGPT1 protein, human
• Angiopoietin-1
• Biomarkers
• Interleukin-6
• Recombinant Proteins
• Vascular Endothelial Growth Factor A

Topics

• Angiopoietin-1 (metabolism, pharmacology)
• Arthritis, Rheumatoid (immunology, pathology)
• Biomarkers (metabolism)
• Cell Proliferation (drug effects)
• Coculture Techniques
• Fibroblasts (drug effects, metabolism, pathology)
• Human Umbilical Vein Endothelial Cells (drug effects, physiology)
• Humans
• Interleukin-6 (pharmacology)
• Neovascularization, Pathologic (drug therapy, pathology)
• Recombinant Proteins
• Synovial Membrane (drug effects, metabolism, pathology)
• Vascular Endothelial Growth Factor A (pharmacology)