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Treatment of Type II Collagen-Induced Rat Rheumatoid Arthritis Model by Interleukin 10 (IL10)-Mesenchymal Stem Cells (BMSCs).

ABSTRACT: BACKGROUND Rheumatoid arthritis model (CIA) rats were treated by tail vein injection of IL-10-modified bone marrow mesenchymal stem cells (BMSCs) to investigate its feasibility and intrinsic molecular mechanism. MATERIAL AND METHODS The CIA rat model was established by induction type II collagen, and IL-10-modified BMSCs was established by transfecting BMSCs with adenovirus. IL-10-modified BMSCs were used to treat the CIA rats. The therapeutic effect was evaluated by measuring the changes in body weight, ankle swelling, and forced swimming time, as well as observation of synovial hyperplasia and cartilage tissue repair by HE staining. Western blot analysis and ELISA were used to detect gene expression. RESULTS After 4 weeks and 8 weeks of treatment with IL10-BMSCs, the body weight, swelling value, resting time, and forced swimming struggle time of CIA rats were significantly higher than those of BMSCs-treated and -untreated CIA rats (P<0.05). Compared to BMSCs-treated CIA model rats, after treatment with IL10-BMSCs, the repair rate of osteoarticular cartilage was higher and the inhibition of synovial proliferation was better, and serum IL-17, IL-1ß, and TNF-alpha levels were lower. We found that the protein level of SIRT1 in peripheral blood mononuclear cells was lower, the protein level in spleen was higher, and phosphorylation of p65 protein in peripheral blood mononuclear cells was reduced. CONCLUSIONS The efficacy of tail vein injection of IL-10-modified BMSCs in treatment of CIA rats was superior to that of BMSCs alone, which may be related to the more pronounced suppression of IL-10-modified BMSCs in peripheral blood inflammation and spleen immune response.

SUBMITTER: Tian S

PROVIDER: S-EPMC6489530 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description:Rheumatoid arthritis (RA) is a disease of the joints that causes decreased quality of life. Mesenchymal stromal cells (MSCs) have immunosuppressive properties, with possible use in the treatment of RA. Similarly, interleukin (IL)-4 has been shown as a potential RA treatment. However, their combination has not been explored before. Therefore, this study aimed to investigate the effect of a combination therapy of MSCs and IL-4 in the treatment of RA, using a murine collagen-induced arthritis (CIA) model. Arthritis was induced in Balb/c mice by two intradermal injections of type II collagen (CII), at days 0 and 21. CIA mice were randomly assigned to four groups; group I received an intravenous injection of mouse bone marrow-derived MSCs, while group II received an intraperitoneal injection of IL-4. Group III received a combined treatment of MSC and IL-4, while group IV served as a CIA diseased control group receiving phosphate buffer saline (PBS). A fifth group of healthy mice served as the normal healthy control. To assess changes induced by different treatments, levels of RA-associated inflammatory cytokines and biomarkers were measured in the serum, knee joints, and synovial tissue, using ELISA and Real Time-qPCR. Histopathological features of knee joints were analyzed for all groups. Results showed that combined MSC and IL-4 treatment alleviated signs of synovitis in CIA mice, reverting to the values of healthy controls. This was evident by the decrease in the levels of rheumatic factor (RF), C-reactive protein (CRP) and anti-nuclear antibodies (ANA) by 64, 80, and 71%, respectively, compared to the diseased group. Moreover, tumor necrosis factor-alpha (TNF- α) and monocyte chemoattractant protein-1 (MCP-1) levels decreased by 63 and 68%, respectively. Similarly, our gene expression data showed improvement in mice receiving combined therapy compared to other groups receiving single treatment, where cartilage oligomeric matrix protein (Comp), tissue inhibitor metalloproteinase-1 (Timp1), matrix metalloproteinase1 (Mmp-1), and IL-1 receptor (Il-1r) gene expression levels decreased by 75, 70, and 78%, respectively. Collectively, treatment with a combined therapy of MSC and IL-4 might have an efficient therapeutic effect on arthritis. Thus, further studies are needed to assess the potential of different MSC populations in conjugation with IL-4 in the treatment of experimental arthritis.

Project description:Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes erosion of articular cartilage and bone and has adverse effects on both patients and livestock animals. The aim of the present study was to investigate the role of interleukin-1β (IL-1β) in the pathogenesis of RA, and to further determine whether injection of IL-1β small interfering RNA (siRNA) or transplantation of IL-1β siRNA + bone marrow mesenchymal stem cells (BMSCs) can ameliorate RA in rats. A collagen-induced arthritis (CIA) rat model was established by injecting type II collagen for 4 weeks. Next, CIA rats were randomly divided into three groups and injected or transplanted with PBS, IL-1β siRNA and IL-1β siRNA + BMSCs for another 4 weeks. The CIA rat model was successfully established, as demonstrated by the higher toe swelling value, thymus and spleen/body weight, immobility time and serum IL-1β concentration, as well as lower body weight, climbing time and mRNA expression of programmed death-1 (PD-1), transforming growth factor-β1 (TGF-β1) and forkhead box protein 3 (Foxp3) in the spleen, compared with control rats. Furthermore, histopathology results demonstrated that joint swelling and redness were observed in the knee joints of CIA rats. H&E results revealed that CIA rats presented erosive destruction of the bone and ulceration of the articular cartilage. In addition, in vitro results demonstrated that IL-1β expression was successfully silenced after IL-1β siRNA transfection in lipopolysaccharide-stimulated BMSCs. When compared with the results of PBS rats, both IL-1β siRNA injection and IL-1β siRNA + BMSC transplantation significantly increased the body weight, climbing time and mRNA expression of PD-1, TGF-β1 and Foxp3 in the spleen, while significantly reduced the immobility time and serum IL-1β concentration. In addition, when compared with that of IL-1β siRNA injection, IL-1β siRNA + BMSC transplantation exhibited markedly higher therapeutic efficacy against CIA. These results demonstrated that higher IL-1β contributed to the pathogenesis of CIA, and that IL-1β siRNA injection ameliorated CIA, while its combination with BMSCs exerted synergistic effects, which may be beneficial against RA.

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Treatment of Type II Collagen-Induced Rat Rheumatoid Arthritis Model by Interleukin 10 (IL10)-Mesenchymal Stem Cells (BMSCs).

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