Abstract
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)-α-dependent manner. In particular, synthetic retinoid agonists with selectivity to RAR-α 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-α-selective agonists in the nephritic models was examined. In this report, we investigated the effect of a newly synthesized RAR-α-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-α-selective retinoid E6060 is a promising candidate of new remedy for lupus nephritis in systemic lupus erythematosus patients.
Footnotes
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doi:10.1124/jpet.104.075598.
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ABBREVIATIONS: RAR, retinoic acid receptor; RXR, retinoid X receptor; ATRA, all-trans-retinoic acid; E6060, 4-{5-[7-fluoro-4-(trifluoromethyl)-benzo[b]furan-2-yl]-1H-2-pyrrolyl}benzoic acid; Am80, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2,3-naphthyl) carbamoyl]benzoic acid; SLE, systemic lupus erythematosus; NZB, New Zealand Black; NZW, New Zealand White; B/WF1, (NZBxNZW)F1; ELISA, enzyme-linked immunosorbent assay; ds, double-stranded; ss, single-stranded; POD, peroxidase; IL, interleukin; BUN, blood urea nitrogen; IFN-γ, interferon-γ; mAb, monoclonal antibody; Th, T helper; ANOVA, analysis of variance.
- Received August 5, 2004.
- Accepted December 16, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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