Does vascular endothelial growth factor play a role in interleukin‐6 receptor antagonist therapy for rheumatoid arthritis?

Gentiletti, Julieta; Fava, Roy A.

doi:10.1002/art.11043

Cited by 9 publications

(9 citation statements)

References 53 publications

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“…The introduction of suppressor of cytokine signaling 3, a potent negative regulator of IL-6 signaling, attenuates mouse RA (collagen-induced arthritis) (37). Recent clinical trials revealed the efficacy of humanized anti-IL-6R on RA (10,36). Collectively, these reports as well as our present results clearly indicate the importance of endogenous IL-6 and its signaling for the induction/ exacerbation of inflammatory arthritis.…”

Section: Discussionsupporting

confidence: 77%

“…Third, IL-6, but not TNF␣, is a causative cytokine in ReA (Table 1, Figure 4, and Figures 5C and D). The efficacy of anti-IL-6 therapy in RA might be explained by the possible inhibition of disease exacerbation by activation of the TLR-4-mediated pathways (10,11,36). Thus, IL-6 might play an important role in the initiation and/or acceleration of inflammation in various types of arthritis, including ReA and RA.…”

Section: Discussionmentioning

confidence: 99%

“…Substantial success of treatment with agents blocking TNF␣ and its signaling in RA has been reported (7,8,33). Furthermore, recent clinical trials targeting IL-6 have also shown the efficacy of anti-IL-6 therapy in RA, although the mechanism remains unidentified (10,32,36). It is well established that TNF␣ has the potential to induce IL-6 production in various cell types (55).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of TLRs results in production of various proinflammatory cytokines, including arthritogenic tumor necrosis factor ␣ (TNF␣), interleukin-12 (IL-12), IL-18, interferon-␥ (IFN␥), and IL-6 (6)(7)(8)(9)(10)(11). Myeloid differentiation factor 88 (MyD88), a signal adaptor molecule, has been demonstrated to be essential for signaling via all of the TLRs except TLR-3 (12,13).…”

mentioning

confidence: 99%

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Endogenous interleukin‐6, but not tumor necrosis factor α, contributes to the development of toll‐like receptor 4/myeloid differentiation factor 88–mediated acute arthritis in mice

Kyo¹,

Futani²,

Terada³

et al. 2005

Arthritis & Rheumatism

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Objective. To generate a mouse model of reactive arthritis (ReA), an aseptic synovitis that develops in joints distant from the primary bacterial infection site, to examine roles for Toll-like receptors (TLRs) that recognize bacterial components involved in the development of this arthritis, and to identify the cytokine(s) relevant to this arthritis.Methods. Mice were treated with cell wall extract from Escherichia coli (ECW) gram-negative bacterium by injection into the footpads. Seven days later, the mice were challenged with lipopolysaccharide (LPS), a TLR-4 ligand, which was injected into the knee joint cavity. To investigate the cytokine(s) involved in this arthritis, mice deficient in various arthritogenic cytokines, such as interleukin-6 (IL-6), IL-12, IL-18, interferon-␥, and tumor necrosis factor ␣ (TNF␣), were sequentially treated with ECW and LPS.Results. ECW-primed mice manifested acute severe arthritis after intraarticular challenge with ECW or LPS, while unprimed mice exhibited modest changes after these challenges. Mutant mice lacking functional TLR-4 or myeloid differentiation factor 88 (MyD88), an adaptor molecule of TLR-4 signaling, were resistant to this arthritis. Although both TNF␣ and IL-6 were equally expressed in the joint after LPS challenge, Il6 ؊/؊ mice, but not Tnf ؊/؊ mice, were resistant to ECW/LPS-induced arthritis.Conclusion. Our present results clearly indicate the importance of priming with ECW and the requirement of TLR-4/MyD88-mediated IL-6, but not TNF␣, for the development of ECW/LPS-induced arthritis. LPSinduced IL-6, in the absence of TNF␣, mediates LPSinduced arthritis. These results suggest that IL-6 is a rational target for therapeutic regimens for inflammatory arthritis, including ReA and rheumatoid arthritis.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Endogenous interleukin‐6, but not tumor necrosis factor α, contributes to the development of toll‐like receptor 4/myeloid differentiation factor 88–mediated acute arthritis in mice

Kyo¹,

Futani²,

Terada³

et al. 2005

Arthritis & Rheumatism

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“…Besides atherosclerosis, it has been recently reported that VEGF is an important determinant of sepsis morbidity and mortality (37). Additionally, VEGF is also functionally involved in host inflammatory responses in acute lung injury (15,35), rheumatoid arthritis (9,11), and inflammatory bowel disease (33). These studies indicate that VEGF possesses proinflammatory and proatherosclerotic properties; however, the signal pathways responsible for VEGF's proinflammatory activity are currently not clear.…”

mentioning

confidence: 99%

Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells

Qin¹,

Wang²,

Tang³

2009

American Journal of Physiology-Cell Physiology

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Emerging evidence indicates that vascular endothelial growth factor (VEGF) plays a critical role in host inflammatory responses in several disease states, including atherosclerosis, sepsis, and rheumatoid arthritis. In this study, we determined the effect of VEGF on endothelial induction of proinflammatory cytokines and investigated the responsible signal pathways. By using a cytokine antibody array that detects the end point protein products released from endothelial cells (ECs), we found that VEGF, via VEGF receptor 2 (VEGFR2), predominantly induced the production of proinflammatory cytokine interleukin (IL)-6 and CXC chemokines IL-8 and growth-related oncogene-α (GRO-α) in ECs but not in leukocytes among 36 cytokines in the array. The production of these inflammatory cytokines by VEGF was much stronger than the induction of cell adhesion molecule in ECs. We further found that the cytokine production by VEGF was essentially mediated by the Gö-6976-sensitive protein kinase D (PKD) family kinases. Importantly, the VEGF-induced production of IL-6, IL-8, and GRO-α was inhibited ∼70%, 40%, or 37% by PKD1 silencing (more than 90% knockdown) with three small interference RNAs that target different PKD1 regions. Moreover, silencing PKD2 downregulated VEGFR2 and markedly inhibited the cytokine production by VEGF in ECs. Our results indicate that VEGF, via VEGFR2-PKD1 axis, induces the production of proinflammatory cytokine IL-6, IL-8, and GRO-α in ECs but not in leukocytes, which may offer new insights into the mechanism of the proinflammatory activity of VEGF.

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JAK inhibitors inhibit angiogenesis by reducing VEGF production from rheumatoid arthritis–derived fibroblast-like synoviocytes

Anjiki,

Hayashi,

Ikuta

et al. 2024

Clin Rheumatol

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Does vascular endothelial growth factor play a role in interleukin‐6 receptor antagonist therapy for rheumatoid arthritis?

Cited by 9 publications

References 53 publications

Endogenous interleukin‐6, but not tumor necrosis factor α, contributes to the development of toll‐like receptor 4/myeloid differentiation factor 88–mediated acute arthritis in mice

Endogenous interleukin‐6, but not tumor necrosis factor α, contributes to the development of toll‐like receptor 4/myeloid differentiation factor 88–mediated acute arthritis in mice

Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells

JAK inhibitors inhibit angiogenesis by reducing VEGF production from rheumatoid arthritis–derived fibroblast-like synoviocytes

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