The type III histone deacetylase silent information regulator 1 (SIRT1) is an enzyme that is critical for the modulation of immune and inflammatory responses. However, the data on its role in rheumatoid arthritis (RA) are limited and controversial. To better understand how SIRT1 regulates adaptive immune responses in RA, we evaluated collagen-induced arthritis (CIA) in myeloid cell-specific SIRT1 knockout (mSIRT1 KO) and wild-type (WT) mice. Arthritis severity was gauged on the basis of clinical, radiographic and pathologic scores. Compared with their WT counterparts, the mSIRT1 KO mice exhibited less severe arthritis, which was less destructive to the joints. The expression levels of inflammatory cytokines, matrix metalloproteinases and ROR-γT were also reduced in the mSIRT1 KO mice compared with the WT mice and were paralleled by reductions in the numbers of Th1 and Th17 cells and CD80- or CD86-positive dendritic cells (DCs). In addition, impaired DC maturation and decreases in the Th1/Th17 immune response were observed in the mSIRT1 KO mice. T-cell proliferation was also investigated in co-cultures with antigen-pulsed DCs. In the co-cultures, the DCs from the mSIRT1 KO mice showed decreases in T-cell proliferation and the Th1/Th17 immune response. In this study, myeloid cell-specific deletion of SIRT1 appeared to suppress CIA by modulating DC maturation. Thus, a careful investigation of DC-specific SIRT1 downregulation is needed to gauge the therapeutic utility of agents targeting SIRT1 in RA.
Aims
To investigate anti‐inflammatory effects of Lactobacillus reuteri LM1071 in lipopolysaccharides (LPS)‐induced inflammation RAW264.7 cells.
Methods and Results
To evaluate anti‐inflammatory activities of L. reuteri LM1071, LPS‐stimulated RAW264.7 cells were used. Gene expression levels of eight immune‐associated genes including IL‐1β, IL‐6 and TNF‐α and protein production levels of COX‐1 and COX‐2 were analysed. Moreover, the production of eicosanoids as important biomarkers for anti‐inflammation was determined.
Conclusions
The current study demonstrates that L. reuteri LM1071 has anti‐inflammatory potential by inhibiting the production of inflammation mediators such as NO, eicosanoids such as PGE1 & PGE2, pro‐inflammatory cytokines and COX proteins. It can also enhance the production of inflammatory associated genes such as IL‐11, BMP4, LEFTY2 and EET metabolite.
Significance and Impact of the Study
Lactobacillus reuteri is one of the crucial bacteria for food fermentation. It can be found in the gastrointestinal system of human and animals. Several studies have shown that L. reuteri has valuable effects on host health. The current study firstly demonstrated that L. reuteri has a beneficial effect on the inflammation containing the variation of eicosanoids (PGE1 and PGE2) which are one of the most important biomarkers and moreover eicosanoid‐associated genes as well as proteins (COX‐2).
The purpose of this study is to investigate the effect of TSAHC [4'-(p-toluenesulfonylamido)-4-hydroxychalcone] in K/BxN serum transfer arthritis model and fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS). In in vivo experiments, TSAHC attenuated the incidence and severity of arthritis in comparison with the vehicle group. Histological findings showed that TSAHC decreased the inflammation, bone erosion, cartilage damage, and osteoclasts activity in the ankle. Furthermore, we confirmed by biochemical analysis that the observations were associated with the decreased expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and RANKL in serum and ankle. In in vitro experiments, TSAHC induced apoptosis, while it significantly suppressed tumor necrosis factor-α (TNF-α)-induced cell proliferation in RA-FLS. Moreover, TSAHC inhibited mRNA expression of TNF-α-induced interleukin (IL)-6, MMP-1, MMP-3, and MMP-13. Evaluation of signaling events showed that TSAHC inhibited the translocation and transcriptional activity of nuclear factor-kappa B (NF-κB) by regulating phosphorylated-IκB-α (p-IκB-α) and IκB-α in TNF-α-induced RA-FLS. Our results suggest that TSAHC inhibits experimental arthritis in mice and suppresses TNF-α-induced RA-FLS activities via NF-κB pathway. Therefore, TSAHC may have therapeutic potential for the treatment of RA.
Background and Purpose Histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses, but the role of HRF/TCTP remains undefined in rheumatoid arthritis (RA). In this study, we explored the pathogenic significance of HRF/TCTP and evaluated the therapeutic effects of HRF/TCTP blockade in RA. Experimental Approach HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine experimental phenotypes of RA. HRF/TCTP levels were measured in the sera of RA patients and compared to those with osteoarthritis (OA), ankylosing spondylitis, Behçet's disease, and healthy controls. HRF/TCTP expression was also assessed in the synovium and fibroblast-like synoviocytes (FLS) obtained from RA or OA patients. Finally, we assessed the effects of HRF/TCTP and dimerized HRF/TCTP-binding peptide-2 (dTBP2), an HRF/TCTP inhibitor, in RA-FLS and CIA mice. Key Results Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were higher in HRF/TCTP TG mice, and lower in KD mice, compared to that in wild-type littermates. HRF/TCTP levels were higher in the sera, synovial fluid, synovium, and FLS of patients with RA than control groups. Serum
BackgroundRheumatoid arthritis (RA) is an invasive inflammatory disease leading to severe joint destruction. Fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS) are key players in RA, and have tumor-like characteristics such as abnormal proliferation and invasion. Translationally Controlled Tumour Protein (TCTP) has been known as a multifunctional protein in cancer progression and allergic response. However, there has been no study to assess the potential roles of TCTP in RA.Materials and methodsThe levels of TCTP were checked in the synovial tissue, serum, and synovial fluid of RA patients.The pathologic roles of TCTP were investigated in RA-FLS and TCTP knockdown (kdTCTP) mice with collagen-induced arthritis (CIA). The preventive and therapeutic effects of inhibitor of TCTP were evaluated in CIA mice on the basis of clinical, radiographic, and pathologic scores.ResultsTCTP expression was higher in the synovial tissue, serum, and synovial fluid of RA patients than control groups. Dimerized TCTP (dTCTP), as an active form of TCTP, exhibits pro-inflammatory cytokine-like activity, thus dTCTP induced cell proliferation, cytokine secretion, migration, and invasion of RA-FLS. Based on these in vitro observations, in vivo experiment using CIA was performed in kdTCTP and wild type (WT) mice. The results showed that inflammatory response and bone destruction were significantly decreased in kdTCTP mice than WT by investigating clinical score, micro-CT, histological, and biochemical analysis. Finally, we confirmed that dTBP2, as an inhibitor of dTCTP, suppressed tumor-like characteristics of RA-FLS, and had protective and therapeutic effects in CIA mice.ConclusionsCollectively, we suggest that TCTP is a critical therapeutic target and the use of dTBP2 may be a beneficial strategy for the RA treatment.
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