scholarly journals Pim-2/mTORC1 Pathway Shapes Inflammatory Capacity in Rheumatoid Arthritis Synovial Cells Exposed to Lipid Peroxidations

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Geng Yin ◽  
Yan Li ◽  
Min Yang ◽  
Xiao-min Cen ◽  
Qi-bing Xie
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Mechanisms ◽  
Synovial Fibroblasts ◽  
Systemic Autoimmune Disease ◽  
Human Rheumatoid Arthritis ◽  
Synovial Cells ◽  
Inflammatory Reactions ◽  
Rheumatoid Arthritis Development ◽  
Ectopic Activation ◽  
Mtorc1 Pathway

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. The proliferation of synovial fibroblasts in response to multiple inflammation factors is central to the pathogenesis of rheumatoid arthritis. Our previous studies showed that 4-HNE may induce synovial intrinsic inflammations by activating NF-κB pathways and lead to cell apoptosis. However, the molecular mechanisms of how synovial NF-κB activation is modulated are not fully understood. Here, the present findings demonstrated that 4-HNE may induce synovial intrinsic inflammations by mTORC1 inactivation. While ectopic activation of mTORC1 pathway by the overexpression of Pim-2 may disrupt the initiation of inflammatory reactions and maintain synovial homeostasis, our findings will help to uncover novel signaling pathways between inflammations and oxidative stress in rheumatoid arthritis development and imply that Pim-2/mTORC1 pathway may be critical for the initiation of inflammatory reactions in human rheumatoid arthritis synovial cells.

scholarly journals CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MAPK, and AP-1 pathway

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Sheng-Mou Hou ◽  
Po-Chun Chen ◽  
Chieh-Mo Lin ◽  
Mei-Ling Fang ◽  
Miao-Ching Chi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Synovial Fibroblasts ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Chemical Inhibitors ◽  
Shrna Plasmid ◽  
Signal Cascades

Abstract Background Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Chemokines and their corresponding receptors have been well characterized in RA progression, but less so in OA pathogenesis. Methods The human primary synovial fibroblasts (SFs) were obtained from human OA and RA tissue samples. The Western blot and qPCR were performed to analyze the expression levels of CXCL1, as well as CXCL-promoted IL-6 expression in both OASFs and RASFs. The signal cascades that mediate the CXCL1-promoted IL-6 expression were identified by using chemical inhibitors, siRNAs, and shRNAs. Results Here, we found that both diseases feature elevated levels of CXCL1 and interleukin (IL)-6, an important proinflammatory cytokine that participates in OA and RA pathogenesis. In OASFs and RASFs, CXCL1 promoted IL-6 expression in a dose- and time-dependent manner. In OASFs and RASFs overexpressing CXCL1 or transduced with shRNA plasmid, IL-6 expression was markedly upregulated. CXCR2, c-Raf, and MAPKs were found to regulate CXCL1-induced IL-6 expression in OASFs and RASFs. Finally, CXCL1 triggered the transcriptional activities of c-Jun (which regulates the expression of proinflammatory proteins) in OASFs and RASFs. Conclusions Our present work suggests that the CXCL1/CXCR2 axis helps to orchestrate inflammatory responses in OA and RA SFs.

scholarly journals Lipid Peroxidation-Mediated Inflammation Promotes Cell Apoptosis through Activation of NF-κB Pathway in Rheumatoid Arthritis Synovial Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Geng Yin ◽  
Ying Wang ◽  
Xiao-min Cen ◽  
Min Yang ◽  
Yan Liang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Apoptosis ◽  
Inflammatory Responses ◽  
Synovial Fibroblasts ◽  
Systemic Autoimmune Disease ◽  
New Strategy ◽  
Significant Clinical Improvement ◽  
Rheumatoid Arthritis Synoviocytes ◽  
Initiation Of Therapy

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of multiple joints. The central pathogenesis of RA is the proliferation of synovial fibroblasts in response to inflammatory cytokines. However, some of the targeted therapies for inflammation reactions do not display significant clinical improvement after initiation of therapy. Thus, the relationship between inflammatory responses and RA therapy is still incompletely understood. In the present study, we proposed to determine whether enhanced inflammations may lead to cell apoptosis in rheumatoid arthritis synoviocytes. Our results indicated that products of lipid peroxidations, 4-HNE, may induce synovial intrinsic inflammations by activating NF-κB pathways and it may lead to cell apoptosis. Pharmacological inhibition of NF-κB activation may reduce the 4-HNE mediated inflammation responses and subsequent cell apoptosis. Our results may help to clarify the role of inflammations on RA development and imply that blocking NF-κB activation may be partly beneficial for human RA therapy. These findings might provide a mechanism-based rationale for developing new strategy to RA clinical therapy.

Enhancement of placenta growth factor expression by oncostatin M in human rheumatoid arthritis synovial fibroblasts

2013 ◽  
Vol 228 (5) ◽  
pp. 983-990 ◽  
Author(s):  
Huang-Ju Tu ◽  
Tzu-Hung Lin ◽  
Yung-Cheng Chiu ◽  
Chih-Hsin Tang ◽  
Rong-Sen Yang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Growth Factor ◽  
Synovial Fibroblasts ◽  
Oncostatin M ◽  
Human Rheumatoid Arthritis ◽  
Placenta Growth Factor ◽  
Factor Expression ◽  
Growth Factor Expression

scholarly journals CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MAPK and AP-1 pathway

2020 ◽  
Author(s):  
Sheng-Mou Hou ◽  
PoChun Chen ◽  
Chieh-Mo Lin ◽  
Mei-Ling Fang ◽  
Miao-Ching Chi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Synovial Fibroblasts ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Chemical Inhibitors ◽  
Shrna Plasmid ◽  
Signal Cascades

Abstract Background: Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Chemokines and their corresponding receptors have been well-characterized in RA progression, but less so in OA pathogenesis.Methods: The human primary synovial fibroblasts (SFs) were obtained from human OA and RA tissue samples. The Western blot and qPCR were performed to analyze expression levels of CXCL1, as well as CXCL-promoted IL-6 expression in both OASFs and RASFs. The signal cascades that mediate the CXCL1-promoted IL-6 expression were identified by using chemical inhibitors, siRNAs and shRNAs.Results: Here, we found that both diseases feature elevated levels of CXCL1 and interleukin (IL)-6, an important proinflammatory cytokine that participates in OA and RA pathogenesis. In OASFs and RASFs, CXCL1 promoted IL-6 expression in a dose- and time-dependent manner. In OASFs and RASFs overexpressing CXCL1 or transduced with shRNA plasmid, IL-6 expression was markedly upregulated. CXCR2, c-Raf and MAPKs was found to regulate CXCL1-induced IL-6 expression in OASFs and RASFs. Finally, CXCL1 triggered the transcriptional activities of c-Jun (which regulates the expression of proinflammatory proteins) in OASFs and RASFs.Conclusions: Our present work suggests that the CXCL1/CXCR2 axis helps to orchestrate inflammatory responses in OA and RA SFs.

scholarly journals Effects of Biological Therapies on Molecular Features of Rheumatoid Arthritis

2020 ◽  
Vol 21 (23) ◽  
pp. 9067
Author(s):  
Chary Lopez-Pedrera ◽  
Nuria Barbarroja ◽  
Alejandra M. Patiño-Trives ◽  
Maria Luque-Tévar ◽  
Eduardo Collantes-Estevez ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Mechanisms ◽  
Adaptive Immune System ◽  
Autoimmune Disorder ◽  
Synovial Fibroblasts ◽  
Chronic Inflammatory Disease ◽  
Pharmacological Therapy ◽  
Biologic Dmards ◽  
Molecular Features ◽  
Specific Effects

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease primarily affecting the joints, and closely related to specific autoantibodies that mostly target modified self-epitopes. Relevant findings in the field of RA pathogenesis have been described. In particular, new insights come from studies on synovial fibroblasts and cells belonging to the innate and adaptive immune system, which documented the aberrant production of inflammatory mediators, oxidative stress and NETosis, along with relevant alterations of the genome and on the regulatory epigenetic mechanisms. In recent years, the advances in the understanding of RA pathogenesis by identifying key cells and cytokines allowed the development of new targeted disease-modifying antirheumatic drugs (DMARDs). These drugs considerably improved treatment outcomes for the majority of patients. Moreover, numerous studies demonstrated that the pharmacological therapy with biologic DMARDs (bDMARDs) promotes, in parallel to their clinical efficacy, significant improvement in all these altered molecular mechanisms. Thus, continuous updating of the knowledge of molecular processes associated with the pathogenesis of RA, and on the specific effects of bDMARDs in the correction of their dysregulation, are essential in the early and correct approach to the treatment of this complex autoimmune disorder. The present review details basic mechanisms related to the physiopathology of RA, along with the core mechanisms of response to bDMARDs.

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