phenanthrenes and Lupus-Erythematosus--Systemic

Triptolide is a biologically active component of the Chinese antirheumatic herbal remedy Tripterygium wilfordii Hook F, which has been shown to be effective in treating murine lupus. However, its immunological mechanisms are poorly understood. Regulatory T cells (Treg) are pivotal for maintaining peripheral self-tolerance and controlling autoimmunity. This study was undertaken to examine the therapeutic effect of triptolide in lupus mice and the related molecular mechanisms. Our results showed that triptolide treatment ameliorated serum anti-dsDNA, proteinuria and renal histopathologic assessment in MRL/lpr mice, induced the miR-125a-5p expression and enhanced the proportion of Treg in vivo. In vitro, triptolide upregulated the proportion of Treg and the miR-125a-5p expression. Down-regulation of the miR-125a-5p expression reversed the effect of triptolide on Treg. In conclusion, triptolide could induce Treg and the miR-125a-5p expression in vivo and in vitro. Inhibiting the effect of miR-125a-5p could counteract the effect of triptolide on inducing Treg. The study has strong implications for the therapeutic applications of triptolide in systemic lupus erythematosus.

Topics: Animals; Antibodies, Antinuclear; Antirheumatic Agents; Cell Proliferation; Disease Models, Animal; Diterpenes; Epoxy Compounds; Female; Humans; Kidney; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; MicroRNAs; Phenanthrenes; Proteinuria; T-Lymphocytes, Regulatory; Up-Regulation

Systemic lupus erythematosus (SLE) is a chronic, devastating autoimmune disorder associated with severe organ damage. Recently, the role of Signal Transducer and Activator of Transcription 3 (STAT3) in murine lupus has been described, suggesting the involvement of STAT3 signaling in the development of SLE. Cryptotanshinone (CTS) is an effective inhibitor of STAT3; however its potential as a SLE treatment remains to be explored. To determine the function of CTS in SLE, we treated MRL/lpr female mice with CTS. Firstly, we found CTS treatment reversed the elevated STAT3 signaling of spleens in lupus-prone MRL/lpr mice, accompanying with a dramatically decreased number of T cells, especially double-negative (DN) T cells. Further research showed that CTS inhibited T cell proliferation via suppressing of STAT3 activation in vitro and in vivo. Consistently, we also proved that CTS treatment significantly alleviated autoimmune response including notably diminished skin lesions, reduced spleen size and increased life span. In addition, CTS treatment decreased the levels of auto-antibodies and pro-inflammatory cytokines, as well as normalized structure and function of kidneys. All these data suggested that CTS treatment depressed STAT3 phosphorylation, which resulted in blocked DN T cell proliferation and finally attenuated the spontaneous SLE development. Taken together, our data identify CTS as a potential therapeutic drug for SLE patients.

Topics: Animals; Cell Proliferation; Cytokines; Female; Kidney; Lupus Erythematosus, Systemic; Mice; Mice, Inbred MRL lpr; Phenanthrenes; STAT3 Transcription Factor; T-Lymphocytes

To test the therapeutic effect of DCB-3503, a synthetic compound derived from a natural product that inhibits NF-kappaB, on end-organ disease in the MRL-Fas(lpr) murine model of systemic lupus erythematosus (SLE).. Eight-week-old female MRL/Fas(lpr) mice were treated intraperitoneally with a low (2 mg/kg) or high (6 mg/kg) dose of DCB-3503 for 10 weeks. Control groups were administered vehicle treatment alone (negative control) or 25 mg/kg cyclophosphamide (positive control). Mice were bled before (8 weeks) and during (13 weeks) treatment, and when they were killed (20 weeks), and serum samples were analyzed for total IgM and IgG levels and autoantibody titers. When the mice were killed, spleen and lymph nodes (axillary, brachial, and cervical) were examined by flow cytometric analysis. The presence of skin and renal disease was determined by histopathologic analysis.. DCB-3503 reduced anti-double-stranded DNA and antichromatin autoantibodies and nearly abrogated inflammatory skin disease in MRL/Fas(lpr) mice; however, it had little effect on histologic kidney disease. Treated mice did not have hematologic or hepatic toxicity. These data indicate that end-organ disease in MRL/Fas(lpr) mice responds differentially to NF-kappaB inhibitor.. DCB-3503 causes significant abrogation of skin disease in MRL/Fas(lpr) mice and may potentially be beneficial in the treatment of inflammatory skin disease in SLE.

Topics: Alkaloids; Animals; Autoantibodies; Disease Models, Animal; DNA; Female; Immunoglobulin G; Immunoglobulin M; Indolizines; Lupus Erythematosus, Systemic; Lupus Nephritis; Lymphatic Diseases; Mice; Mice, Inbred MRL lpr; NF-kappa B; Phenanthrenes; Skin Diseases; Splenomegaly