Differential effects of IL-6 blockade tocilizumab and TNF inhibitors on angiogenesis in synovial tissues from patients with rheumatoid arthritis

Hirohata, Shunsei; Abe, Asami; Murasawa, Akira; Kanamono, Toshihisa; Tomita, Tadanori; Yoshikawa, Hideki

doi:10.1080/14397595.2016.1259717

Cited by 15 publications

(9 citation statements)

References 25 publications

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“…In this regard, the observation of elevated levels of NGAL in RA patients after TCZ administration is contrary to the general anti-angiogenic effects mediated by TCZ. However, notably, NGAL plays many other pleiotropic roles unrelated to its role in angiogenesis, such as in protecting against bacterial infection by acting as an iron-carrying protein, in modulating oxidative stress, in promoting neutrophil chemotaxis, and in regulating thermogenesis and lipid metabolism by acting as an adipokine [10,30]. Moreover, although NGAL normally protects MMP-9 from degradation, we did not observe any elevation in MMP-9 serum levels in RA patients.…”

Section: Discussioncontrasting

confidence: 63%

“…Although it is known to lead to the accumulation of IL-6 in the serum of treated patients [2], TCZ reduces the production of pro-in ammatory cytokines, reduces CRP and SAA levels, and ameliorates the systemic manifestation of RA, such as pain, fatigue, and anemia [1,2,8]. While the effects of TCZ on angiogenesis have yet to be investigated in depth, TCZ has been shown to reduce VEGF serum levels in complete Freund's adjuvant (CFA)-induced arthritic rats [9], and to reduce the mean vessel density (MVD) in the synovium of RA patients as evaluated by immunohistochemical staining for the endothelial marker CD31 [10]. However, the detailed mechanisms of action, which enable TCZ to inhibit angiogenesis, are not yet understood.…”

Section: Introductionmentioning

confidence: 99%

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Tocilizumab (TCZ) Decreases Angiogenesis in Rheumatoid Arthritis through its Regulatory Effect on miR-146a-5p and EMMPRIN/CD147

Zisman

Safieh

Simanovich

et al. 2021

Preprint

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BackgroundAngiogenesis is an important contributor to the development of Rheumatoid arthritis (RA). Tocilizumab (TCZ), an anti-IL-6 receptor antibody, is used in the treatment of RA patients, and has been shown to exert anti-inflammatory effects. However, its effects on angiogenesis are not fully elucidated, and the molecular mechanisms regulating this effect are unknown. MethodsWe evaluated the concentrations of several pro- and anti-angiogenic factors and the expression levels of several microRNA molecules that are associated with RA and angiogenesis in serum samples obtained from 40 RA patients, before and 4 months after the initiation of TCZ treatment. Additionally, we used an in vitro co-culture system of fibroblasts (the HT1080 cell line) and monocytes (the U937 cell line) to explore the mechanisms of TCZ action. ResultsSerum samples from RA patients treated with TCZ exhibited reduced levels of EMMPRIN/CD147, enhanced expression of miR-146a-5p and miR-150-5p, and reduced angiogenesis as was manifested by the reduced number of tube-like structures formed by EaHy926 endothelial cell line. In vitro, the accumulation of the pro-angiogenic factors EMMRPIN, VEGF and MMP-9 in the supernatants was increased by co-culturing the HT1080 fibroblasts and the U937 monocytes, while the accumulation of the anti-angiogenic factor thrombospondin-1 (Tsp-1) and the expression levels of miR-146a-5p were reduced. Transfection of HT1080 cells with the miR-146a-5p mimic, decreased the accumulation of EMMPRIN, VEGF and MMP-9. When EMMPRIN was neutralized with a blocking antibody, supernatants derived from these co-cultures exhibited reduced migration, proliferation and tube formation in functional assays. ConclusionsOur findings implicate miR-146a-5p in the regulation of EMMPRIN and propose that TCZ affects angiogenesis through its effects on EMMRPIN and miR-146a-5p.

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Section: Discussioncontrasting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Tocilizumab (TCZ) Decreases Angiogenesis in Rheumatoid Arthritis through its Regulatory Effect on miR-146a-5p and EMMPRIN/CD147

Zisman

Safieh

Simanovich

et al. 2021

Preprint

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“…TNF- α is released from macrophagocytes in the synovium and pannus and may have potent antioxidant and anti-inflammatory effects [ 33 ]. IL-6 can trigger the immune system by activating B-cells [ 34 ], releasing immunoglobulins, and increasing the production of rheumatoid factor [ 35 , 36 ]. It could also enhance the production of TNF- α and IL-1 β [ 15 ], thereby aggravating cartilage destruction [ 15 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Anti‐Inflammatory Effects of p‐Coumaric Acid, a Natural Compound of Oldenlandia diffusa, on Arthritis Model Rats

Zhu

Xiong

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Objectives In China, Oldenlandia diffusa (OD) is a natural herb that is widely used and has been proven to be effective in the treatment of rheumatoid arthritis (RA). This study aimed to preliminarily reveal the mechanism by which OD exerts its beneficial effect. Methods Ultra-performance liquid chromatography photodiode array was applied to identify the absorbable compounds in the plasma of collagen-induced arthritis (CIA) model rats. After 2 weeks, an OD decoction or the identified absorbable compound was administered to CIA rats. Morphology, X-ray images of the joints, pathological images, arthritis index, and cytokine (TNF-α and IL-6) levels were evaluated. Results p-Coumaric acid (p-CA) was identified as the absorbed compound in plasma. After administration of p-CA solution or the OD decoction, symptoms in the treated rats were alleviated as compared to the untreated model rats, and inflammatory cell infiltration was suppressed. The arthritis index and serum levels of TNF-α and IL-6 were decreased as compared to the control group. Conclusions OD may exert its anti-inflammatory effect on RA via its active ingredient, p-CA. This information sheds light on the mechanism by which OD exerts its anti-inflammatory effort in RA and forms the basis for further development of therapeutic agents for RA.

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“…Previous reports have shown that plenty abnormal signaling pathways are involved in the transformation of FLSs from friend to foe, such as excessive proliferation and subdued apoptosis of FLSs via P53 [ 8 , 9 ], P21 [ 10 – 12 ], Ras [ 13 ], Myc [ 14 ]. Further pathway examples include glucose-6-phosphate isomerase (G6PI) [ 15 ], HIF-1α [ 16 ] and TNFα [ 17 ], which mediate hypoxia-induced angiogenesis, contributed to pannus formation in RA synovia. Furthermore, plenty of activated signaling pathways promote the secretion of inflammatory factors and aggravated immune response [ 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

SIRT1 promotes tumor-like invasion of fibroblast-like synoviocytes in rheumatoid arthritis via targeting TIMP1

et al. 2017

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Suppression of tissue inhibitor of matrix metalloproteinase (TIMP) is associated with the tumor-like invasion of fibroblast-like synoviocytes (FLSs) that occurs during rheumatoid arthritis-related cartilage destruction. Silent information regulator 2 homolog1 (SIRT1), a histone deacetylase, is widely involved in transcriptional regulation, genomic stability, metabolism and DNA repair. Recent studies suggest that SIRT1 may also impact inflammatory response and the proliferation of FLSs in rheumatoid arthritis (RA). However, it is unknown whether SIRT1 has a role in the tumor-like invasion of FLSs in rheumatoid arthritis. Herein we report that SIRT1 contributes to FLS invasion and cartilage destruction via a TIMP1-dependent mechanism. Elevated SIRT1 in RA synovia suppresses TIMP1 expression via deacetylation of TIMP1-associated histones, thereby disrupting the binding of the transcription factor specificity protein 1 (Sp1) to the TIMP1 promoter. In rats with collagen-induced arthritis, depletion of SIRT1 remarkably promoted TIMP1 expression in synovial tissues and ameliorated cartilage destruction. These results describe a new role for SIRT1 and demonstrate its potential value as a therapeutic target for rheumatoid arthritis.

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Differential effects of IL-6 blockade tocilizumab and TNF inhibitors on angiogenesis in synovial tissues from patients with rheumatoid arthritis

Abstract: These results demonstrated that inhibition of angiogenesis is a unique action of TCZ. Moreover, the data also suggest that lining layers proliferation might be closely associated with angiogenesis.

Cited by 15 publications

References 25 publications

Tocilizumab (TCZ) Decreases Angiogenesis in Rheumatoid Arthritis through its Regulatory Effect on miR-146a-5p and EMMPRIN/CD147

Tocilizumab (TCZ) Decreases Angiogenesis in Rheumatoid Arthritis through its Regulatory Effect on miR-146a-5p and EMMPRIN/CD147

Anti‐Inflammatory Effects of p‐Coumaric Acid, a Natural Compound of Oldenlandia diffusa, on Arthritis Model Rats

SIRT1 promotes tumor-like invasion of fibroblast-like synoviocytes in rheumatoid arthritis via targeting TIMP1

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