Abstract
Context: β-Sitosterol (BS), the primary constituent of plants and vegetables, exhibits multiple biological effects.Objective: This study explores its effect of immune-regulation on macrophages and its potential for rheumatoid arthritis (RA) therapy.Materials and methods: In vitro, bone marrow-derived macrophages (BMDMs) were treated with 5, 25 and 50 μM BS in the M1 or M2 polarization conditions. In vivo, either i.p. injection with 20 or 50 mg/kg BS every 2 d after boost immunization of collagen-induced arthritis (CIA) or adoptive transfer of 2 × 106 BS-treated BMDMs (BS-BMDMs) at the day before CIA were adopted in mice to test the therapeutic effect. IL-10 antibody depletion was used in the period of above treatments to discuss the underlying mechanism.Results: The phenotypes and function of BMDMs showed that 5, 25 and 50 μM BS significantly repressed the M1 polarization and augmented M2 polarization dependent upon concentration. The expression of iNOS, IL-1β, CD86 and MHCII in 25 μM BS-treated M1-polarized BMDMs was reduced by 50.2, 47.1, 87.1 and 31.3%, respectively. In contrast, the expression of arginase-1, IL-10, CD163 and CD206 in 25 μM BS-treated M2-polarized BMDMs was increased by 65.6, 107.4, 23.5 and 51.3%, respectively. In CIA mice, either i.p. injection with BS or adoptive transfer of BS-BMDMs could alleviate the symptoms of ankle swelling (vehicle group: 3.13 ± 0.102 mm; 20 mg/kg BS group: 2.64 ± 0.043 mm; 50 mg/kg BS group: 2.36 ± 0.084 mm; BMDMs group: 3.09 ± 0.174 mm; BS-BMDMs group: 2.43 ± 0.042 mm), reduce the levels of collagen-specific antibodies (IgG and IgG1, but not IgG2c, p < 0.05) and inhibit the production of pro-inflammatory cytokines (p < 0.05). Depletion of IL-10 counteracted the effect of BS treatment (α-IL-10 vs. RatIgG1, p < 0.01 on day 16), highlighting the role of IL-10 in the anti-inflammatory response.Conclusions: These results suggested that BS could modulate the functions of macrophages and might be a promising agent for RA therapy.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1% of the human population
The results of quantitative RT-PCR showed that in the presence of IFN-c, iNOS and IL-1b produced by 25 lM BSBMDMs reduced 50.2 and 47.1%, while these bone marrow-derived macrophages (BMDMs) expressed $0.5-fold increase of arginase-1 and 1-fold increase of IL-10 upon the stimulation of IL-4, as compared with BMDMs treating with vehicle (Figure 1(C,D))
As compared with M1 or M2 macrophages, CD86 and MHCII expressed by BS-BMDMs reduced 87.1 and 31.3% in M1 polarization condition, while upon stimulation of IL-4 they expressed 23.5% increase of CD206 and 51.3% increase of CD163 (Figure 1(E))
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1% of the human population. A chronic inflammation occurs in the joint and establishes synovitis, which contains abundant activated immune cells, causing progressive cartilage tissue damage. Innate immune cells, such as monocytes, macrophages and neutrophils, were observed in the joints of RA patients (Van den Berg and Van Lent 1996; Apel et al 2018). During this disease, substantially activated monocytes increase in blood and migrate along with chemokine gradient to infiltrate into the joint (Mulherin et al 1996). Given that macrophages have the bidirectional roles in the inflammatory response, targeting macrophage to repress inflammatory response might be a promising strategy for RA therapy
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