IL-35 Inhibits Angiogenesis through VEGF/Ang2/Tie2 Pathway in Rheumatoid Arthritis

Area of Science:

• Immunology
• Vascular Biology
• Rheumatology

Background:

• Synovial angiogenesis, driven by vascular endothelial growth factor (VEGF) and angiopoietins (Angs), is crucial in rheumatoid arthritis (RA) pathogenesis.
• Interleukin-35 (IL-35), an anti-inflammatory cytokine, is known to attenuate arthritis, but its precise mechanisms remain unclear.

Purpose of the Study:

• To elucidate the mechanisms by which IL-35 regulates angiogenesis in the context of RA.
• To investigate the role of IL-35 in modulating pro-angiogenic factors like VEGF and angiopoietins (Angs).

Main Methods:

• In vitro assays using human umbilical vein endothelial cells (HUVECs) to assess migration, adhesion, and tube formation.
• In vivo studies using a murine Matrigel plugs model to evaluate vessel formation.
• Analysis of matrix metalloproteinases (MMP2/MMP9) and inflammatory cytokines (IL-6/IL-8) via zymography and ELISA.
• Investigation of signaling crosstalk between IL-35, VEGF, and Ang2 in HUVECs and RA synovial tissue explants.

Main Results:

• IL-35 inhibited endothelial cell migration, adhesion, and tube formation, both basally and in response to VEGF.
• VEGF-induced angiopoietin-2 (Ang2) secretion, which promotes angiogenesis, was suppressed by IL-35.
• IL-35 antagonized the pro-angiogenic effects of Ang2 and inhibited downstream signaling molecules like MMP2/MMP9 and IL-6/IL-8.

Conclusions:

• IL-35 restrains RA angiogenesis and inflammation by downregulating Ang2 secretion and disrupting the Ang2/Tie2 signaling pathway.
• These findings enhance the understanding of RA angiogenesis regulation.
• The study suggests IL-35 as a potential therapeutic target for novel angiogenesis-inhibiting treatments for RA.