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

Kayakabe, Ken; Kuroiwa, Takashi; Sakurai, Noriyuki; Ikeuchi, Hidekazu; Kadiombo, Anastasie Tshilela; Sakairi, Toru; Matsumoto, Takayuki; Maeshima, Akito; Hiromura, Keiju; Nojima, Yoshihisa

doi:10.1093/rheumatology/kes093

Cited by 59 publications

(46 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RA angiogenesis is driven and maintained by proangiogenic factors released from RA synovial tissue myeloid cells and fibroblasts, which include vascular endothelial growth factor (VEGF), angiopoietin (Ang)1 and 2, plateletderived growth factor, and transforming growth factor-β [3][4][5]. VEGF is the most potent proangiogenic factor in RA angiogenesis, highly expressed in RA [6], stimulating endothelial cell (EC) proliferation, migration, and vascular tube formation [7].…”

Section: Introductionmentioning

confidence: 99%

“…Ang1, Ang2, Tie1, and Tie2 are upregulated in RA synovial tissues [10]. Evidence suggests that the Ang/Tie2 signaling pathway mediates the proangiogenic effects of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and tolllike receptor (TLR)2 in RA [5,11,12]. Ang2 neutralization decreases synovial inflammation, neovascularization, and joint destruction in CIA [13].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Jiang¹,

Li²,

Lin³

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The pro-angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietins (Angs) play a prominent role in synovial angiogenesis, an early and critical event in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-35 is an anti-inflammatory cytokine that attenuates collagen-induced arthritis, however, the mechanisms involved are not fully understood. Methods: The effects of IL-35 on endothelial cell migration, adhesion, and tube formation were examined using human umbilical vein endothelial cells (HUVEC) in vitro. The effects of IL-35 on vessel formation in vivo were examined using a murine Matrigel plugs model. MMP2/MMP9 and IL-6/IL-8 secretion were assessed by zymography and ELISA, respectively. The crosstalk between IL-35, VEGF, and Ang2 in HUVECs and RA synovial tissue explants was investigated. Results: IL-35 inhibited basal and VEGF-induced HUVEC migration and adhesion in vitro as well as tube formation in vitro and in vivo. VEGF increased Ang2 secretion by HUVECs and RA synovial tissue explants, and exogenous Ang2 promoted HUVEC migration, adhesion, and tube formation with similar potency to VEGF. Blocking the Ang/Tie2 pathway with a Tie2 kinase antibody inhibited the proangiogenic effects of exogenous Ang2 and VEGF in HUVECs. IL-35 inhibited basal and VEGF-induced Ang2 secretion by HUVECs and RA synovial tissue explants; it also antagonized the proangiogenic effects of exogenous Ang2 in HUVECs. Moreover, IL-35 reduced basal and VEGF/Ang2-induced MMP2/MMP9 and IL-6/IL-8 secretion. Conclusion: These results suggested that IL-35 restrains RA angiogenesis and inflammation by downregulating basal and VEGF-induced Ang2 secretion as well as disrupting Ang2/Tie2 signal transduction. Our findings extend current understanding of mechanisms regulating RA angiogenesis and may support development of novel angiogenesis-targeting therapeutics for RA treatment.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Jiang¹,

Li²,

Lin³

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Among the cytokines closely related to the pathogenesis of s-JIA, previous studies have shown that IL-1b downregulates Ang-1 expression [17]. Furthermore, IL-6 inhibits Ang-1 signaling by downregulating Ang-1 expression and upregulating Ang-2 expression [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the role of Ang-2/1 in the homeostasis of endothelial function, several lines of evidence have suggested that Ang-1 and Ang-2 play roles in the exacerbation of synovitis in patients with rheumatoid arthritis (RA) [18,20,21]. Ang-1, Ang-2, and Tie2, are expressed in RA synovial tissue [20,21].…”

Section: Discussionmentioning

confidence: 99%

“…Ang-1, Ang-2, and Tie2, are expressed in RA synovial tissue [20,21]. In the synovial tissue of RA patients, Tie2 activation has been shown to be predominantly localized to macrophages [18]. Ang-1/2 has been shown to stimulate the activation of intracellular signaling pathways, and cooperate with TNF to induce macrophage IL-6 and macrophage inflammatory protein 1a production [21].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Disruption of vascular endothelial homeostasis in systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The dynamic roles of angiopoietin-1 and -2

et al. 2016

View full text Add to dashboard Cite

Leptin‐induced migration and angiogenesis in rheumatoid arthritis is mediated by reactive oxygen species

et al. 2017

View full text Add to dashboard Cite

Rheumatoid arthritis ( RA ) is a progressive autoimmune disease affecting the joints. In this study, we investigated the role of the pro‐angiogenic factor leptin in regulating reactive oxygen species ( ROS ) to promote cell migration and angiogenesis in RA . We showed that leptin triggered RA fibroblast‐like synoviocyte ( FLS ) migration by increased ROS expression. Additionally, leptin enhanced human umbilical vein endothelial cell ( HUVEC ) tube formation in a ROS /hypoxia‐inducible factor‐1α‐dependent manner, accompanied by increased production of vascular endothelial growth factor and interleukin ( IL )‐6. We also revealed that antagonists of tumor necrosis factor, IL ‐6 and IL ‐1β down‐regulated ROS production of RA FLS induced by leptin, which subsequently attenuated RA FLS migration and HUVEC tube formation. These findings demonstrated that leptin might play an important role in RA FLS migration and HUVEC angiogenesis.

show abstract

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

Abstract: 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.

Cited by 59 publications

References 26 publications

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

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

Disruption of vascular endothelial homeostasis in systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The dynamic roles of angiopoietin-1 and -2

Leptin‐induced migration and angiogenesis in rheumatoid arthritis is mediated by reactive oxygen species

Contact Info

Product

Resources

About