The Therapeutic Effect of Sauchinone on Inflammatory Arthritis in Mice

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease, mainly involving joints and bones. Sauchinone is an anti-inflammatory agent isolated from Saururus chinensis, which was used in oriental medicine. The aim of this study was to evaluate the therapeutic effect of sauchinone on inflammatory arthritis and underlying mechanism of anti-arthritic effect. METHODS: Mice with collagen induced arthritis (CIA) was intraperitoneally injected with sauchinone (20 mg/kg) or vehicle. The clinical and histological evaluations were performed with arthritis scoring and hematoxylin-eosin staining, respectively. CD4+ interleukin (IL) 17+ T cells were determined under Th17 skewing condition treated with sauchinone. To evaluate the effect of sauchinone on osteoclastogenesis, mice bone marrow macrophages (BMMs) and human peripheral blood mononuclear cells (PBMCs) were cultured with macrophage-colony stimulating factor and receptor activator of nuclear factor-κB ligand in the absence or presence of sauchinone. RESULTS: Sauchinone significantly attenuated the inflammatory arthritis in CIA mice both clinically and histologically. The proportion of Th17 cells were decreased with treatment with sauchinone in vivo and in vitro. The expressions of Th17 cell markers (IL-17 and retinoic acid receptor-related orphan receptor gamma t) and B cell markers (activation-induced cytidine deaminase) were downregulated in the presence of sauchinone. Sauchinone also suppressed the formation of tartrate-resistant acid phosphatase positive cells from mice BMMs and human PBMCs, and the expression of osteoclastogenic markers. CONCLUSION: Sauchinone alleviates inflammatory arthritis in mice through inhibition of Th17 differentiation and osteoclastogenesis. Sauchinone, one of traditional herbal medicine, could be a therapeutic candidate for the treatment of RA.

Serum Level of Interleukin-33 and Soluble ST2 and Their Association with Disease Activity in Patients with Behcet's Disease

Interleukin (IL)-33 is an important mediator of innate immunity. Behcet's disease (BD) is an autoinflammatory disorder characterized by hyperactivity of the innate immune response. We measured serum levels of IL-33 and its receptor soluble ST2 (sST2) in patients with BD to investigate their association with disease activity. Serum levels of both IL-33 and sST2 were higher in patients with BD compared with those in normal controls (IL-33: 594.48+/-175.04 pg/mL in BD and 224.23+/-56.64 pg/mL in normal controls [P=0.048], sST2: 99.01+/-15.92 pg/mL in BD and 23.56+/-3.25 pg/mL in normal controls [P<0.001]). IL-33 and sST2 expression in skin tissue, as shown by immunohistochemistry, was higher in patients with BD compared with that in the normal controls. Serum sST2 level correlated significantly with the BD currently active form (BDCAF), Iranian BD dynamic activity measure (IBDDAM), erythrocyte sedimentation rate and C-reactive protein. Multiple linear regression showed that serum sST2 was an independent factor associated with IBBDAM (regression coefficient, 0.374; P=0.004), and BDCAF (regression coefficient, 0.236; P=0.047). These results demonstrate that IL-33 and sST2 are highly expressed in patients with BD and that serum sST2 is an independent factor associated with IBDDAM and BDCAF, suggesting a potential role for sST2 as a surrogate marker of disease activity in patients with BD.

Reciprocal Regulation of TH17 and Regulatory T Cells by Methotrexate and Its Therapeutic Effects in Collagen-induced Arthritis (CIA)

OBJECTIVE: Methotrexate is the first-line drug in treatment of rheumatoid arthritis (RA) exhibiting higher efficacy and better tolerability than most other DMARDs. To have a better understanding of the anti-arthritic mechanism of methotrexate, we investigated the effect of methotrexate on suppressing the autoimmune inflammatory and destructive arthritis in collagen-induced arthritis (CIA) mice. METHODS: The effects of methotrexate on joint inflammation were assessed by clinical scoring and histologic analysis. Levels of cytokines and autoreactive antibodies were analyzed by immunohistochemistry and ELISA. The population of TH17 and Foxp3+ regulatory T (Treg) cells and phosphorylation of their critical transcription activators, STAT3 and STAT5, were examined by fluorescence microscopy and flow cytometry, respectively. RESULTS: Treatment with methotrexate significantly alleviated joint inflammation and cartilage destruction in CIA. Serum levels of total immunoglobulins G, G1, G2a specific to type II collagen were also reduced considerably in methotrexate-treated mice. The drug inhibited the expression of proinflammatory cytokines such as IL-1beta, TNF-alpha, IL-6 and IL-17 in arthritic joints ex vivo as well as by splenocytes in vitro. Moreover, methotrexate treatment resulted in reciprocal modulation of TH17 cells and Foxp3+ regulatory T (Treg) cells in spleen tissues, in which TH17 cells were decreased and Treg cells in number were increased. Subsequent analysis of CD4+T cells showed that phosphorylation of STAT3 was decreased whereas phosphorylation of STAT5 was increased in methotrexate-treated mice. CONCLUSION: Methotrexate treatment effectively suppressed autoimmune arthritis and restored homeostasis of the immune system by reciprocal regulation of TH17 and Treg cells in a mouse model of collagen-induced arthritis.