Bosentan, an endothelin receptor antagonist, ameliorates collagen-induced arthritis: The role of TNF-α in the induction of endothelin system genes

Post Graduation Program in Basic and Applied Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenue Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
Agents and Actions (Impact Factor: 2.35). 01/2012; 61(4):337-48. DOI: 10.1007/s00011-011-0415-5
Source: PubMed


Endothelins (ETs) are involved in several inflammatory events. The present study investigated the efficacy of bosentan, a dual ETA/ETB receptor antagonist, in collagen-induced arthritis (CIA) in mice.
CIA was induced in DBA/1J mice. Arthritic mice were treated with bosentan (100 mg/kg) once a day, starting from the day when arthritis was clinically detectable.
CIA progression was assessed by measurements of visual clinical score, paw swelling and hypernociception. Histological changes, neutrophil infiltration and pro-inflammatory cytokines were evaluated in the joints. Gene expression in the lymph nodes of arthritic mice was evaluated by microarray technology. PreproET-1 mRNA expression in the lymph nodes of mice and in peripheral blood mononuclear cells (PBMCs) was evaluated by real-time PCR. The differences were evaluated by one-way ANOVA or Student's t test.
Oral treatment with bosentan markedly ameliorated the clinical aspects of CIA (visual clinical score, paw swelling and hyperalgesia). Bosentan treatment also reduced joint damage, leukocyte infiltration and pro-inflammatory cytokine levels (IL-1β, TNFα and IL-17) in the joint tissues. Changes in gene expression in the lymph nodes of arthritic mice returned to the levels of the control mice after bosentan treatment. PreproET mRNA expression increased in PBMCs from rheumatoid arthritis (RA) patients but returned to basal level in PBMCs from patients under anti-TNF therapy. In-vitro treatment of PBMCs with TNFα upregulated ET system genes.
These findings indicate that ET receptor antagonists, such as bosentan, might be useful in controlling RA. Moreover, it seems that ET mediation of arthritis is triggered by TNFα.

Download full-text


Available from: Silvio Manfredo Vieira, Oct 14, 2015
1 Follower
28 Reads
  • Rheumatology International 11/2012; 39(11). DOI:10.1007/s00296-012-2579-x · 1.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Endothelin-1 (ET-1) is a 21-amino acid peptide with multifunctional regulation. Initial research indicated that ET-1 is related to the inflammatory pathogenesis of periodontitis and involved in the regulation of cytokines, but the mechanisms involved remain unclear. The primary aim of this study is to investigate how ET-1 affects proinflammatory cytokine expression in human periodontal ligament (hPDL) cells. Methods: hPDL cells were obtained from both healthy (H)- and periodontitis (P)-affected periodontal tissues. H-hPDL and P-hPDL cells were treated with ET-1 (1, 10, and 100 nM) for 12, 24, and 48 hours. The untreated cells served as a control. To confirm the specificity of the ET-1 effects, 100 nM of the specific endothelin A (ETA) receptor antagonist BQ123 and 100 nM of the specific ETB receptor antagonist BQ788, as negative control, were used. To examine the signaling pathways and molecular mechanisms involved in ET-1-mediated cytokine expression, H-hPDL and P-hPDL cells were pretreated with specific inhibitors for extracellular signal-regulated kinase (ERK1/2) (PD98059), c-Jun N-terminal kinase (SP600125), and p38 kinase (SB203580) for 1 hour before 100 nM ET-1 stimulation. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 messenger RNA (mRNA) and protein levels were evaluated by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Results: ET-1 dose- and time-dependently induced the production of proinflammatory cytokines TNF-α, IL-1β, and IL-6 by H-hPDL and P-hPDL cells at both mRNA and protein levels. However, ETA and ETB receptor antagonists inhibited the stimulatory effects of ET-1 on inflammatory cytokine expression in H-hPDL and P-hPDL cells. Furthermore, inhibitors of the mitogen-activated protein kinases (MAPKs) significantly reduced ET-1-stimulated TNF-α, IL-1β, and IL-6 expression in H-hPDL and P-hPDL cells. Conclusion: ET-1 may be involved in the inflammatory process of periodontitis, at least in part, by stimulating proinflammatory cytokine production via the MAPK pathway in hPDL cells.
    Journal of Periodontology 05/2013; 85(4). DOI:10.1902/jop.2013.130195 · 2.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The aim of this study was to assess whether apocynin, an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase blocker, influences lipid peroxidation TBARS, hydrogen peroxide (H2O2) content, protein level, heart edema, tumor necrosis factor α (TNF-α) concentration or the glutathione redox system in heart homogenates obtained from endothelin 1 (ET-1)-induced oxidative stress rats. Methods: Experiments were carried out on adult male Wistar-Kyoto rats. The animals were divided into 4 groups: Group I: saline-treated control; Group II: saline followed by ET-1 (3 μg/kg b.w., iv); Group III: apocynin (5 mg/kg b.w., iv) administered half an hour before saline; Group IV: apocynin (5 mg/kg b.w., iv) administered half an hour before ET-1 (3 μg/kg b.w., iv). Results: Injection of ET-1 alone showed a significant (p < 0.001) increase in thiobarbituric acid reactive substances (TBARS) and the hydrogen peroxide level (p < 0.01) vs. control, as well as a decrease (p < 0.001) in the GSH level. Apocynin significantly decreased TBARS (p < 0.001) and H2O2 (p < 0.05) level (vs. control) as well as improved protein level (p < 0.001) in the heart. Apocynin also prevented ET-1-induced heart edema (p < 0.05). The presence of ET-1 increased the concentration of TNF-α (p < 0.05) while apocynin decreased it (p < 0.05). Our results indicate that ET-1 may induce oxidative stress in heart tissue by reducing the GSH/GSSG ratio, stimulating lipid peroxidation and increasing TNF-α concentration. Apocynin diminished these measures of oxidative stress and TNF-α. Conclusion: ET-1-induced formation of ROS in the heart is at least partially regulated via NADPH oxidase.
    Pharmacological reports: PR 07/2013; 65(4):898-905. DOI:10.1016/S1734-1140(13)71071-5 · 1.93 Impact Factor
Show more