Novel synthetic retinoic acid inhibits rat collagen arthritis and differentially affects serum immunoglobulin subclass levels

Kuwabara, Kenji; Shudo, Koichi; Hori, Yozo

doi:10.1016/0014-5793(95)01440-3

Cited by 44 publications

(37 citation statements)

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“…It remarkably suppressed abnormal elevation of antibody production in those mice, and this effect seems to contribute, at least partly, to its antinephritic effect. Recently, an RAR-␣ selective synthetic retinoid, Am80, was reported to inhibit type II collagen-induced arthritis with a prominent reduction in anti-collagen IgG titer (Kuwabara et al, 1996;Nagai et al, 1999). Similarly, our RAR-␣-selective retinoid substantially inhibited not only anti-DNA antibody production (Fig.…”

Section: Discussionsupporting

confidence: 67%

“…Recently, Am80, a ligand with an affinity specific for RAR-␣, was reported to inhibit collagen-induced arthritis concomitantly with a prominent reduction in anti-collagen IgG titers (Kuwabara et al, 1996;Nagai et al, 1999). This report was the first to show that a retinoid could reduce Article, publication date, and citation information can be found at…”

Section: Introductionmentioning

confidence: 99%

“…antibody production and thereby prevent rat collagen-induced arthritis (Kuwabara et al, 1996). We have also synthesized and reported RAR-␣ subtype-selective retinoid agonists , Seino et al, 2000.…”

mentioning

confidence: 98%

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Effect of E6060 [4-{5-[7-Fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic Acid], a Novel Subtype-Selective Retinoid, on Lupus-Like Nephritis in Female (NZBxNZW)F1 Mice

Yamauchi¹,

Ishibashi²,

Shikata³

et al. 2004

J Pharmacol Exp Ther

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Disease amelioration by retinoids in various nephritic models has been reported from either immunological or pathophysiologic viewpoints. It has also been reported that retinoids exert immunosuppressive effects in a retinoic acid receptor (RAR)-␣-dependent manner. In particular, synthetic retinoid agonists with selectivity to RAR-␣ have been reported to have a remarkable disease-ameliorating effect in some immune disease models via their potent immunosuppressive activities; however, there has been no report in which the effect of RAR-␣-selective agonists in the nephritic models was examined. In this report, we investigated the effect of a newly synthesized RAR-␣-selective retinoid agonist, E6060 [4-{5-[7-fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic acid], on the disease progression in a murine lupus nephritis model. Female (NZBxNZW)F1 mice were prophylactically treated with E6060 from 5 months of age, and their nephritic (proteinuria, blood urea nitrogen) and immunological parameters (serum anti-DNA autoantibodies and total serum immunoglobulins) were monitored with age up to 10 months old. E6060 at 0.03 and 0.1 mg/kg (once daily, p.o.) significantly improved survival rate and prevented the development of proteinuria in (NZBxNZW)F1 mice. Anti-DNA autoantibodies and total serum IgG were also significantly reduced in the E6060-treated mice. Among IgG isotypes, IgG2a was substantially reduced by E6060 treatment, indicating reduced T helper 1 responses in E6060-treated mice. In accordance with this possibility, elevation of serum interleukin-12 (p40) in old female (NZBxNZW)F1 mice was significantly inhibited by E6060 treatment. Our data suggest that the RAR-␣-selective retinoid E6060 is a promising candidate of new remedy for lupus nephritis in systemic lupus erythematosus patients.Retinoids are vitamin A derivatives used for the treatment of vitamin A deficiency and dermatological disorders, as well as for chemoprophylaxis and therapy of certain cancers. Retinoids are ligands for retinoic acid receptor (RAR) and/or retinoid X receptor (RXR), both of which belong to the steroid receptor superfamily (Mangelsdorf and Evans, 1995). RAR and RXR each have three subtypes, ␣, ␤, and ␥. Retinoids act by modulating the transcription of target genes through interaction with these RAR and RXR subtypes, thereby interfering with cellular regulation, growth, and differentiation processes.Retinoids, such as 4-hydroxyretinamide, all-trans-retinoic acid (ATRA), and 13-cis-retinoic acid, were reported to be effective in some immunological disease models, such as rat adjuvant arthritis (Brinckerhoff et al., 1983) and experimental allergic encephalomyelitis (Racke et al., 1995), which are believed to be caused through inappropriate cellular immune responses. Recently, Am80, a ligand with an affinity specific for RAR-␣, was reported to inhibit collagen-induced arthritis concomitantly with a prominent reduction in anti-collagen IgG titers (Kuwabara et al., 1996;Nagai et al., 1999). This report was the first...

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

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Effect of E6060 [4-{5-[7-Fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic Acid], a Novel Subtype-Selective Retinoid, on Lupus-Like Nephritis in Female (NZBxNZW)F1 Mice

Yamauchi¹,

Ishibashi²,

Shikata³

et al. 2004

J Pharmacol Exp Ther

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“…Regarding the effect of retinoic acid on autoimmune diseases, a few reports have shown the therapeutic efficacy of retinoic acid in animal models of multiple sclerosis (14) and systemic lupus erythematosus (15,16). As for the role of retinoic acid in RA, which is the prototype of autoimmune diseases, a few investigations have shown that retinoic acid had a therapeutic impact on animal models of RA (17)(18)(19)(20). However, the precise mechanism of the therapeutic effect mediated by retinoic acid in rheumatoid inflammation still remains to be determined.…”

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confidence: 99%

Retinoic Acid Attenuates Rheumatoid Inflammation in Mice

Kwok

Park

Cho

et al. 2012

The Journal of Immunology

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Retinoic acid is the active vitamin A derivative and is well-known to have diverse immunomodulatory actions. In this study, we investigated the impact of all-trans retinoic acid (ATRA), a biologic key metabolite of vitamin A, on the development of arthritis and the pathophysiologic mechanisms by which ATRA might have antiarthritic effects in animal model of rheumatoid arthritis (RA; collagen-induced arthritis [CIA] in DBA/1J mice). We showed that treatment with ATRA markedly suppressed the clinical and histologic signs of arthritis in the CIA mice. It reduced the expression of IL-17 in the arthritic joints. Interestingly, Foxp3+ regulatory T cells were markedly increased and IL-17–producing CD4+ T cells (Th17 cells) were decreased in the spleens of ATRA-treated mice. In vitro treatment with ATRA induced the expression of Foxp3 and repressed the IL-17 expression in the CD4+ T cells in mice. ATRA suppressed the production of total IgG and IgG2a in splenocytes that were stimulated by LPS. It also reduced serum levels of total IgG and IgG2 anti-collagen Abs and germinal center formation in CIA mice. In addition, the ATRA-treated mice showed decreased osteoclast formation in arthritic joints. Moreover, ATRA downregulated the expression of receptor activator of NF-κB ligand, the leading player of osteoclastogenesis, in the CD4+ T cells and fibroblast-like synoviocytes from patients with RA. Furthermore, ATRA prevented both human monocytes and mice bone marrow-derived monocytes/macrophage cells from differentiating into osteoclasts. These data suggest ATRA might be an effective treatment modality for RA patients.

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“…Am80 has been reported to inhibit the development of collagen-induced arthritis in mice and rats, experimental autoimmune encephalomyelitis in rats and 2,4-dinitrofluorobenzene-induced contact dermatitis in mice. [9][10][11][12] In this study we examined the effect of Am80 administration on the development of type 1 diabetes in NOD mice in order to clarify its immunomodulatory competence.…”

mentioning

confidence: 99%

Oral Administration of Synthetic Retinoid Am80 Inhibits the Development of Type 1 Diabetes in Non-obese Diabetic (NOD) Mice

Ishido

Shudo

2009

Biological & Pharmaceutical Bulletin

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Synthetic retinoid Am80 is a potent modulator of the immune system. Am80 is effective in various experimentally induced autoimmune disorders. The purpose of this study is to confirm its effect on non-obese diabetic (NOD) mice, which spontaneously develop autoimmune type 1 diabetes. Am80 was orally administered in feed to 6 NOD mice per group at a dose of 0 (control), 0.1 (low) or 1 (high) mg/kg/d for 19 weeks. During the experiment period, the high urine glucose levels were observed in 33% mice of the control and low Am80 groups, whereas any mouse in the high Am80 group did not show abnormal urine glucose level. Histological examination showed that the average score of insulitis severity in the low Am80 group was similar to that in the control; however in the high Am80 group, the score was significantly reduced compared to that in the control group. Similarly, the severity of lymphocyte infiltration in the submandibular glands showed a tendency to decrease in the high Am80 group, but not in the low Am80 group, compared to the control. These data strongly suggest that the development of type 1 diabetes in NOD mice can be inhibited by oral administration of Am80.Key words retinoid; Am80; non-obese diabetic mouse; type 1 diabetes Type 1 diabetes is a T-cell-mediated, inflammatory autoimmune disease characterized by the infiltrate of activated T lymphocytes into the islets of Langerhans of the pancreas (insulitis), resulting in the inflammation and progressive destruction of the insulin-producing beta cells. Several factors have been proposed to be involved in the inflammatory response leading to beta cell destruction, including cytolytic lymphocytes and proinflammatory cytokines, as well as the local generation of chemokines and cellular adhesion molecules.1) The non-obese diabetic (NOD) mouse is one of the commonly used animal models of spontaneous type 1 diabetes.2) Development of type 1 diabetes in NOD mice is preceded by infiltration of pancreatic islets by mononuclear cells, and then antigen-dependent expansion of pathogenic autoreactive T-cells is observed followed by beta cell destruction and diabetes.Retinoids, analogs of vitamin A, interact with retinoic acid receptors (RARs) and/or retinoid X receptors (RXRs), and modulate the immune systems by a variety of methods including modulation of Th1/Th2 development and production of cytokines by inflammatory cells such as macrophages. Several selective RAR ligands have been reported to be effective on collagen-induced arthritis in rodents 3)

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Novel synthetic retinoic acid inhibits rat collagen arthritis and differentially affects serum immunoglobulin subclass levels

Cited by 44 publications

References 35 publications

Effect of E6060 [4-{5-[7-Fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic Acid], a Novel Subtype-Selective Retinoid, on Lupus-Like Nephritis in Female (NZBxNZW)F1 Mice

Effect of E6060 [4-{5-[7-Fluoro-4-(trifluoromethyl)benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic Acid], a Novel Subtype-Selective Retinoid, on Lupus-Like Nephritis in Female (NZBxNZW)F1 Mice

Retinoic Acid Attenuates Rheumatoid Inflammation in Mice

Oral Administration of Synthetic Retinoid Am80 Inhibits the Development of Type 1 Diabetes in Non-obese Diabetic (NOD) Mice

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