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2.
Isr Med Assoc J ; 21(7): 454-459, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507120

RESUMO

BACKGROUND: Platelets have the ability to influence the immune system and the inflammatory process and may be strongly involved in the whole pathogenic process of chronic inflammatory joint diseases, such as rheumatoid arthritis. They may play a significant role even before the clinical onset of the disease, contributing to the loss of tolerance of the immune system and the induction of autoimmunity. Subsequently, they can interact with the most important cellular players involved in autoimmunity and inflammation, namely innate immunity cells and T cells and eventually contribute to the building of inflammation in the synovium, thus inducing the activation, migration, and proliferation of fibroblasts that eventually lead to joint damage. Due to their peculiar features, studying the behavior of platelets is a challenging task; however, platelets may prove to be valuable therapeutic targets in the future.


Assuntos
Artrite Reumatoide/imunologia , Plaquetas/imunologia , Sinovite/imunologia , Artrite Reumatoide/patologia , Autoimunidade/imunologia , Fibroblastos/imunologia , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/patologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/patologia , Linfócitos T/imunologia
3.
Inflamm Res ; 68(10): 889-900, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31372663

RESUMO

OBJECTIVE: To investigate the participation of canonical Wnt and NF-κB signaling pathways in an experimental model of chronic arthritis induced by methylated bovine serum albumin (mBSA) in rat temporomandibular joint (TMJ). MATERIALS AND METHODS: Wistar rats were sensitized by mBSA+Complete Freund Adjuvant (CFA)/Incomplete Freund Adjuvant (IFA) on the first 14 days (1 ×/week). Subsequently, they received 1, 2 or 3 mBSA or saline solution injections into the TMJ (1 ×/week). Hypernociceptive threshold was assessed during the whole experimental period. 24 h after the mBSA injections, the TMJs were removed for histopathological and immunohistochemical analyses for TNF-α, IL-1ß, NF-κB, RANKL, Wnt-10b, ß-catenin and DKK1. RESULTS: The nociceptive threshold was significantly reduced after mBSA injections. An inflammatory infiltrate and thickening of the synovial membrane were observed only after mBSA booster injections. Immunolabeling of TNF-α, IL-1ß and Wnt-10b was increased in the synovial membrane in arthritic groups. The immunoexpression of nuclear ß-catenin was significantly higher only in the group that received 2 booster TMJ injections. However, NF-κB, RANKL and DKK1 immunoexpression were increased only in animals with 3 mBSA intra-articular injections. CONCLUSION: Our results suggest that canonical Wnt and NF-κB signaling pathways participate in the hypernociception and inflammatory response in TMJ synovial membrane during the development of rheumatoid arthritis in rats.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Hiperalgesia/imunologia , NF-kappa B/imunologia , Articulação Temporomandibular/imunologia , Via de Sinalização Wnt , Animais , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Adjuvante de Freund , Hiperalgesia/patologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Interleucina-1beta/imunologia , Lipídeos , Masculino , Ligante RANK/imunologia , Ratos Wistar , Soroalbumina Bovina , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Articulação Temporomandibular/patologia , Fator de Necrose Tumoral alfa/imunologia , Proteínas Wnt/imunologia
4.
J Immunol Res ; 2019: 4080735, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428656

RESUMO

Rheumatoid arthritis (RA) and osteoarthritis (OA) are common rheumatic disorders that primarily involve joints. The inflammation of the synovium can be observed in both of the two diseases. Synovial fibroblasts (SFs) play an important role in the inflammatory process of the synovium. The functional states of synovial fibroblasts are heterogeneous, and the detailed transition process of their functional states is still unclear. By using transcriptomic data of SFs at a single-cell level, we found a similar transition process for SFs in RA and OA. We also identified the potential regulatory effects of the WNT signaling pathway, the TGF-ß signaling pathway, the FcεRI signaling pathway, and the ERBB signaling pathway on modifying the SFs' functional state. These findings indicate potentially overlapped pathogenic mechanisms in these two diseases, which may help uncover new therapeutic targets to ameliorate disease progression.


Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Osteoartrite/metabolismo , Membrana Sinovial/citologia , Artrite Reumatoide/imunologia , Progressão da Doença , Fibroblastos/imunologia , Genes erbB , Humanos , Osteoartrite/imunologia , Análise de Célula Única , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt
5.
Int J Mol Sci ; 20(13)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288389

RESUMO

Nanobody against V-set and Ig domain-containing 4 (Vsig4) on tissue macrophages, such as synovial macrophages, could visualize joint inflammation in multiple experimental arthritis models via single-photon emission computed tomography imaging. Here, we further addressed the specificity and assessed the potential for arthritis monitoring using near-infrared fluorescence (NIRF) Cy7-labeled Vsig4 nanobody (Cy7-Nb119). In vivo NIRF-imaging of collagen-induced arthritis (CIA) was performed using Cy7-Nb119. Signals obtained with Cy7-Nb119 or isotope control Cy7-NbBCII10 were compared in joints of naive mice versus CIA mice. In addition, pathological microscopy and fluorescence microscopy were used to validate the arthritis development in CIA. Cy7-Nb119 accumulated in inflamed joints of CIA mice, but not the naive mice. Development of symptoms in CIA was reflected in increased joint accumulation of Cy7-Nb119, which correlated with the conventional measurements of disease. Vsig4 is co-expressed with F4/80, indicating targeting of the increasing number of synovial macrophages associated with the severity of inflammation by the Vsig4 nanobody. NIRF imaging with Cy7-Nb119 allows specific assessment of inflammation in experimental arthritis and provides complementary information to clinical scoring for quantitative, non-invasive and economical monitoring of the pathological process. Nanobody labelled with fluorescence can also be used for ex vivo validation experiments using flow cytometry and fluorescence microscopy.


Assuntos
Artrite Experimental/diagnóstico , Artrite Experimental/metabolismo , Macrófagos/metabolismo , Imagem Molecular/métodos , Receptores de Complemento , Anticorpos de Domínio Único , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Animais , Imunofluorescência , Corantes Fluorescentes/química , Imuno-Histoquímica , Macrófagos/imunologia , Masculino , Camundongos , Microscopia de Fluorescência , Modelos Moleculares , Estrutura Molecular , Receptores de Complemento/imunologia , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/imunologia , Espectroscopia de Luz Próxima ao Infravermelho , Coloração e Rotulagem , Membrana Sinovial/imunologia
6.
PLoS One ; 14(7): e0218736, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31260471

RESUMO

LL-37 is the only human cathelicidin-family host defense peptide and has been reported to interact with invading pathogens causing inflammation at various body sites. Recent studies showed high levels of LL-37 in the synovial-lining membrane of patients with rheumatoid arthritis, a common type of inflammatory arthritis. The present study aims to investigate the role of LL-37 on mechanisms associated with pathogenesis of inflammatory arthritis. The effects of LL-37 on the expression of proinflammatory cytokines, hyaluronan (HA) metabolism-related genes, cell death-related pathways, and cell invasion were investigated in SW982, a human synovial sarcoma cell line. Time-course measurements of proinflammatory cytokines and mediators showed that LL-37 significantly induced IL6 and IL17A mRNA levels at early time points (3-6 hr). HA-metabolism-related genes (i.e., HA synthase 2 (HAS2), HAS3, hyaluronidase 1 (HYAL1), HYAL2, and CD44) were co-expressed in parallel. In combination, LL-37 and IL17A significantly enhanced PTGS2, TNF, and HAS3 gene expression concomitantly with the elevation of their respective products, PGE2, TNF, and HA. Cell invasion rates and FN1 gene expression were also significantly enhanced. However, LL-37 alone or combined with IL17A did not affect cell mortality or cell cycle. Treatment of SW982 cells with both LL-37 and IL17A significantly enhanced IKK and p65 phosphorylation. These findings suggest that the chronic production of a high level of LL-37 may synchronize with its downstream proinflammatory cytokines, especially IL17A, contributing to the co-operative enhancement of pathogenesis mechanisms of inflammatory arthritis, such as high production of proinflammatory cytokines and mediators together with the activation of HA-metabolism-associated genes and cell invasion.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Hialurônico/metabolismo , Interleucina-17/farmacologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Combinação de Medicamentos , Sinergismo Farmacológico , Fibroblastos/imunologia , Fibroblastos/patologia , Fibronectinas/genética , Fibronectinas/imunologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/imunologia , Hialuronan Sintases/genética , Hialuronan Sintases/imunologia , Ácido Hialurônico/imunologia , Hialuronoglucosaminidase/genética , Hialuronoglucosaminidase/imunologia , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Inflamação , Interleucina-6/genética , Interleucina-6/imunologia , Transdução de Sinais , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
7.
Int Immunopharmacol ; 74: 105701, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228817

RESUMO

Synovitis is an aseptic inflammation that leads to joint effusion, pain and swelling. As one of the main drivers of pathogenesis in osteoarthritis (OA), the presence of synovitis contributes to pain, incidence and progression of OA. In our previous study, DC32 [(9α,12α-dihydroartemisinyl) bis(2'-chlorocinnmate)], a dihydroartemisinin derivative, was found to have an antirheumatic ability via immunosuppression, but the effect of DC32 on synovitis has not been fully illuminated. In this study, we chose to evaluate the effect and mechanism of DC32 on attenuating synovial inflammation. Fibroblast-like synoviocytes (FLSs) of papain-induced OA rats were isolated and cultured. And DC32 significantly inhibited the invasion and migration of cultured OA-FLSs, as well as the transcription of IL-6, IL-1ß, CXCL12 and CX3CL1 in cultured OA-FLSs measured by qPCR. DC32 remarkably inhibited the activation of ERK and NF-κB pathway, increased the expression of Nrf2 and HO-1 in cultured OA-FLSs detected by western blot. DC32 inhibited the degradation and phosphorylation of IκBα which further prevented the phosphorylation of NF-κB p65 and the effect of DC32 could be relieved by siRNA for Nrf2. In papain-induced OA mice, DC32 significantly alleviated papain-induced mechanical allodynia, knee joint swelling and infiltration of inflammatory cell in synovium. DC32 upregulated the mRNA expression of Type II collagen and aggrecan, and downregulated the mRNA expression of MMP2, MMP3, MMP13 and ADAMTS-5 in the knee joints of papain-induced OA mice measured by qPCR. The level of TNF-α in the serum and secretion of TNF-α in the knee joints were also reduced by DC32 in papain-induced OA mice. In conclusion, DC32 inhibited the inflammatory response in osteoarthritic synovium through regulating Nrf2/NF-κB pathway and attenuated OA. In this way, DC32 may be a potential agent in the treatment of OA.


Assuntos
Antirreumáticos/uso terapêutico , Artemisininas/uso terapêutico , Inflamação/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Membrana Sinovial/imunologia , Sinoviócitos/fisiologia , Animais , Movimento Celular , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
8.
Int Immunopharmacol ; 73: 539-551, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177080

RESUMO

OBJECTIVE: We aimed to investigate the immunologic mechanisms by which arsenic trioxide (As2O3) may inhibit T helper 17 (Th17) cell differentiation while promoting regulatory T (Treg) cell generation by modulating signal transducer and activator of transcription 3 (STAT3) in treatment-naïve rheumatoid arthritis (RA) patients. METHODS: Naïve CD4+T cells isolated by fluorescence-activated cell sorting from treatment-naïve RA patients and healthy controls were used to investigate the effect of As2O3 on the process of polarization and the related cytokines. STAT3 transfection experiments were conducted with small interfering RNA (siRNA) and lentivirus STAT3 to verify the mechanism of As2O3 on Th17-Treg balance in vitro. A collagen-induced arthritis (CIA) model was used to detect the clinical scores, histopathological change, bone destruction, Th17-Treg proportion and joint tissue immunohistochemistry. RESULTS: We found that As2O3 prevented activated naïve CD4+T-cells from differentiating into Th17 cells and reduced cytokine production by activated Th17 cells by downregulating their signature transcription factors, STAT3 and orphan nuclear receptors. Notably, As2O3 reduced Th17 cells frequency while increasing Treg cells frequency under specific polarizing conditions in treatment-naïve RA patients by transfecting siRNA STAT3 and lentivirus STAT3. Furthermore, we noticed that applying As2O3 in the CIA model attenuated the infiltration of joint inflammation and bone destruction, and significantly improved the imbalanced Treg-Th17 ratio. CONCLUSIONS: These data indicate that As2O3 may be a potential immune modulator for treatment-naïve RA patients that helps to balance of Treg and Th17 cells through modulating STAT3.


Assuntos
Trióxido de Arsênio/farmacologia , Artrite Reumatoide/imunologia , Fatores Imunológicos/farmacologia , Fator de Transcrição STAT3/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adulto , Animais , Trióxido de Arsênio/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Citocinas/imunologia , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Baço/efeitos dos fármacos , Baço/imunologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
9.
BioDrugs ; 33(4): 391-399, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31172372

RESUMO

Psoriasis is a chronic inflammatory skin disease with significant psychological and physical impact. Over the last few decades, several highly effective target therapies have been developed, leading to a major paradigm shift in the way psoriatic disease is managed. Despite this, a proportion of patients still do not respond or lose response over time. Bispecific antibodies target two different cytokines simultaneously, potentially offering a better disease control. Interleukin (IL)-17A and IL-17F share structural homology and have similar biologic function. IL-17A is classically considered to be the most biologically active, but recent studies have shown that IL-17F is also increased in psoriatic skin and synovial cell in psoriatic arthritis, supporting the rationale for targeting both IL-17A and IL-17F in psoriatic disease. Bimekizumab is the first-in-class monoclonal antibody designed to simultaneously target IL-17A and IL-17F. Bimekizumab is currently in clinical development for psoriasis, psoriatic arthritis, and ankylosing spondylitis, with promising results. In early clinical trials, bimekizumab demonstrated a rapid onset of action, good safety profile, and high tolerability by treated study participants. Long-term results and head-to-head trials comparing bimekizumab with other agents will be crucial to define the role of bimekizumab in the treatment of psoriatic disease.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Psoríase/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Ensaios Clínicos como Assunto , Humanos , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Psoríase/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Espondilite Anquilosante/imunologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Resultado do Tratamento
10.
APMIS ; 127(8): 588-593, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233243

RESUMO

Microfibrillar-associated protein 4 (MFAP4) is a non-structural matrix protein with cell regulatory activities and a potential as seromarker for fibrosis. We aimed to study the occurrence of MFAP4 in the synovial membrane from patients with rheumatoid arthritis (RA) vs osteoarthritis (OA). Formaldehyde-fixed synovial tissue sections, from patients with RA (N = 6) and OA (N = 6) undergoing total hip arthroplasty, were deparaffinized and immunostained with monoclonal antibodies against MFAP4. Elastin was detected using ElastiKit. MFAP4 in serum (sMFAP4) and synovial fluid was measured by an immunoassay. MFAP4 was present in synovial biopsies from both RA and OA patients, particularly prominent in deep arterioles where it colocalized with elastin. Notably however, MFAP4 was absent from the internal elastic lamina in RA arterioles irrespective of disease duration and synovitis activity, while present although with irregular staining patterns in OA specimens. sMFAP4 was increased in RA and OA serum vs healthy controls: median (interquartile range) 29.8 (25.3-39.1) and 25.5 U/L (18.1-43.3) vs 17.7 U/L (13.7-21.2), p = 0.006 and p = 0.02, respectively The concentration of synovial fluid was lower than in serum in both RA and OA. These findings may suggest that MFAP4 is involved in adaptive vessel wall remodeling associated with chronic joint disease.


Assuntos
Artrite Reumatoide/imunologia , Proteínas de Transporte/análise , Proteínas da Matriz Extracelular/análise , Glicoproteínas/análise , Osteoartrite/imunologia , Membrana Sinovial/imunologia , Idoso , Anticorpos Monoclonais/imunologia , Biomarcadores/análise , Proteínas de Transporte/imunologia , Estudos de Casos e Controles , Proteínas da Matriz Extracelular/imunologia , Feminino , Glicoproteínas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Líquido Sinovial/química , Membrana Sinovial/patologia
11.
BMC Musculoskelet Disord ; 20(1): 286, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200688

RESUMO

BACKGROUND: McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop destructive arthritis and enthesitis in the ankle. There is no published data that drug treatment has been trialed on these mice. This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of arthritis and enthesitis in McH-lpr/lpr-RA1 mice. METHODS: Male McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16-1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines. RESULTS: Tissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at 14 and 17 weeks of age. The kappa coefficient was 0.77. However, progression of entheseal ossification persisted in the MR16-1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16-1 treated groups. CONCLUSIONS: Administration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for destructive arthritis and enthesitis. IL-6 signal blockade could contribute to the treatment of destructive arthritis, and further studies should be carried out to confirm its potential in the prevention of enthesopathy developed to ossification.


Assuntos
Anticorpos/administração & dosagem , Artrite/tratamento farmacológico , Entesopatia/tratamento farmacológico , Receptores de Interleucina-6/antagonistas & inibidores , Animais , Artrite/imunologia , Artrite/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Entesopatia/imunologia , Entesopatia/patologia , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos , Distribuição Aleatória , Receptores de Interleucina-6/imunologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Membrana Sinovial/patologia
12.
Inflamm Res ; 68(7): 597-611, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31119302

RESUMO

OBJECTIVE: The present study was undertaken to validate whether TNF-α and calreticulin (CRT) serve as dual signaling to activate nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and HUVECs. The effect of human antigen R (HuR) in NLRP3 inflammasome activation was also explored in RA FLS. METHODS: Immunofluorescence was used to determine the expression of NLRP3 and adaptor protein apoptosis associated speck-like protein containing a CARD (ASC) in RA synovial tissue and HuR location in RA FLS. Western blot and quantitative real-time PCR were employed to measure the priming effect of NLRP3 inflammasome in cells and HuR expression in synovial tissue. The concentrations of IL-1ß and IL-18 were detected by enzyme linked immunosorbent assay. Immunohistochemistry was used to visualize the expression of HuR in synovial tissue. HuR knockdown in RA FLS was achieved by siRNA-mediated gene silencing. RESULTS: Higher expression of NLRP3 and ASC in RA synovial tissue than those in osteoarthritis was detected. The staining of NLRP3, ASC and cleaved IL-1ß were observed in FLS and vascular endothelial cells in RA synovium. Expression of NLRP3 and pro-IL-1ß in RA FLS and HUVECs treated with TNF-α was increased. The pro-IL-18 expression was also enhanced in HUVECs, but not in RA FLS. TNF-α/CRT dual stimulation of cells gave rise to caspase-1 p20 expression and the secretion of IL-1ß. The secreted IL-18 was also elevated in HUVECs but not in RA FLS. HuR expression was significantly elevated in RA synovial tissue. TNF-α initiated the nucleocytoplasmic shuttling of HuR in both FLS and HUVECs. The knockdown of HuR in FLS incubated with TNF-α led to reduced caspase-1 p20 protein expression and further resulted in decreased secretion of IL-1ß in the presence of CRT. CONCLUSIONS: TNF-α/CRT dual signaling induced NLRP3 inflammasome activation, which could be suppressed by HuR knockdown presumably due to the block of HuR translocating from nucleus to cytoplasma.


Assuntos
Artrite Reumatoide/imunologia , Calreticulina/imunologia , Proteína Semelhante a ELAV 1/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fator de Necrose Tumoral alfa/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Transdução de Sinais , Membrana Sinovial/imunologia , Sinoviócitos/imunologia
13.
Isr Med Assoc J ; 5(21): 345-352, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31140228

RESUMO

BACKGROUND: Angiogenesis is the outgrowth of new blood vessels from existing ones and is an early occurrence in inflamed joint tissue. It is governed by a tightly controlled balance of pro- and anti-angiogenic stimuli, which promote or inhibit generation and proliferation of new endothelial cells, vascular morphogenesis, and vessel remodeling. At the beginning, capillary formation is crucial in maintaining the supply of various nutrients as well as oxygen to the inflamed tissue. Local and systemic expression of angiogenic factors may indicate a constant remodeling of synovial vasculature. Redox signaling is closely related to angiogenesis and can alter angiogenic responses of synovial cells. In this review we discuss key issues about the endothelial pathology in inflammatory arthritis followed by a review of angiogenic processes and main angiogenic mediators. We discuss the hypoxia-vascular endothelial growth factor (VEGF)-Ang/Tie2 system and its related therapeutic implications in detail with further review of various mediator protein targets and intracellular regulatory pathway targets with their current and potential future role in preclinical or clinical setting whilst ameliorating inflammation.


Assuntos
Artrite Reumatoide , Neovascularização Patológica , Membrana Sinovial , Proteínas Angiogênicas/metabolismo , Anti-Inflamatórios/farmacologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/imunologia , Membrana Sinovial/irrigação sanguínea , Membrana Sinovial/imunologia , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/imunologia
14.
Int J Mol Sci ; 20(8)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027208

RESUMO

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation of the synovial membrane, with thickening of the synovial layer, cellular hyperplasia, and infiltration of immune cells. Mast cells (MCs) are cells of the innate immunity present in healthy synovia and part of the cellular hyperplasia characterizing RA synovitis. Although their presence in synovia has been well described, the exact functions and the correlation of MCs with disease development and progression have been debated, particularly because of contradictory data obtained in animal models and from patients with longstanding disease. Here, we present a revision of the literature on MCs in RA, including the most recent observations obtained from patients with early RA, indicating MCs as relevant markers of disease severity in early RA.


Assuntos
Artrite Reumatoide/patologia , Mastócitos/patologia , Animais , Artrite Reumatoide/imunologia , Humanos , Imunomodulação , Inflamação/patologia , Ativação Linfocitária/imunologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia
15.
Scand J Immunol ; 90(1): e12770, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31017304

RESUMO

Increasing evidence suggests a role of inflammation during the pathogenesis of osteoarthritis (OA). The local and systemic inflammation was studied in 33 patients of different KL grades, grade2 (n = 11), grade3 (n = 6) and grade4 (n = 16). The levels of cytokines, adipokines and matrix metalloproteinases (MMPs) were measured in serum and synovial fluid (SF) by flow cytometry and ELISA, respectively. The frequency of T cells and CD161 expression was measured by flow cytometry. The levels of IL-1ß, IL-6 and IL-10 were significantly higher in sera and SF of patients with OA as compared to healthy control's serum. Higher levels of MMP9 and leptin and lower levels of adiponectin were observed in SF as compared to serum. The MMP9 in SF and MMP13 levels in serum and SF decreased in KL grade 4 cases. In these patients, higher levels of leptin and lower levels of adiponectin were observed in SF versus patients of lower grades. There was increased infiltration of CD8+ T cells in SF of OA cases with decreased frequency in grade 4 cases. The expression of CD161 on T cells was significantly higher in SF than peripheral blood with significant upregulation in grade 4 patients. The CD161 expression had significant positive correlation with IL-17 in the serum of patients. The ROC curves of CD161 expression significantly distinguished grade 2 and grade 4 patients. Collectively, an elevated CD161 expression on T cells in circulation and synovial compartment clearly distinguished lower and higher grade patients warranting studies to assess its role as a contributing factor towards OA progression.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Inflamação/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Osteoartrite/imunologia , Membrana Sinovial/imunologia , Movimento Celular , Doença Crônica , Citocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Ativação Linfocitária , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Regulação para Cima
16.
Biol Pharm Bull ; 42(4): 538-542, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930413

RESUMO

Temporomandibular disorders (TMD) are a common stomatognathic disease affecting all age groups. Patients with internal derangement (ID) or osteoarthritis (OA) of temporomandibular joint (TMJ) often have TMJ synovitis. When TMJ synovial membrane is damaged, many inflammatory cytokines are produced and secreted from TMJ synoviocytes to synovial fluid of TMJ. It has been widely reported that many kinds of biologic factors are produced from TMJ synoviocytes stimulated with interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. One of the major symptoms of TMD is pain of the TMJ. Many study groups have studied relations between the development of TMJ pain and biologic factors secreted into synovial fluid of TMJ. Here, we summarize previous reports trying to elucidate this correlation. On the other hand, it has been reported that a new molecular mechanism of IL-1beta secretion called inflammasome is involved in several diseases with sterile inflammation. Because TMJ synovitis with ID and OA of TMJ is also sterile inflammation, inflammasome may be involved in the development of TMJ synovial inflammation. This review describes some molecular mechanisms underlying inflammation in TMJ, especially in TMJ synovitis, which may be useful for the development of new therapies against TMD.


Assuntos
Transtornos da Articulação Temporomandibular/imunologia , Animais , Citocinas/imunologia , Humanos , Dor/imunologia , Membrana Sinovial/anatomia & histologia , Membrana Sinovial/imunologia , Sinovite/imunologia , Articulação Temporomandibular/anatomia & histologia , Articulação Temporomandibular/imunologia
17.
Nat Immunol ; 20(4): 458-470, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30890796

RESUMO

The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4+ T cells, prior activation via the T cell antigen receptor limits IL-6's control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4+ T cells. Transcriptomics and chromatin immunoprecipitation-sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4+ T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4+ T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4+ T cells sense and interpret cytokine signals.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Animais , Artrite Reumatoide/enzimologia , Artrite Reumatoide/patologia , Linfócitos T CD4-Positivos/enzimologia , Células CHO , Células Cultivadas , Cricetulus , Regulação da Expressão Gênica , Humanos , Memória Imunológica , Interleucina-6/fisiologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Interleucina-6/fisiologia , Membrana Sinovial/imunologia , Transcrição Genética
18.
Med Sci Monit ; 25: 2246-2256, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30916045

RESUMO

BACKGROUND Rheumatoid arthritis (RA) has a high prevalence in the elderly population. The genes and pathways in the inflamed synovium in patients with RA are poorly understood. This study aimed to identify differentially expressed genes (DEGs) linked to the progression of synovial inflammation in RA using bioinformatics analysis. MATERIAL AND METHODS Gene expression profiles of datasets GSE55235 and GSE55457 were acquired from the Gene Expression Omnibus (GEO) database. DEGs were identified using Morpheus software, and co-expressed DEGs were identified with Venn diagrams. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into subnetworks using the Molecular Complex Detection (MCODE) algorithm. The functions of the top module were assessed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. RESULTS DEGs that were upregulated were significantly enhanced in protein binding, the cell cytosol, organization of the extracellular matrix (ECM), regulation of RNA transcription, and cell adhesion. DEGs that were downregulated were associated with control of the immune response, B-cell and T-cell receptor signaling pathway regulation. KEGG pathway analysis showed that upregulated DEGs enhanced pathways associated with the cell adherens junction, osteoclast differentiation, and hereditary cardiomyopathies. Downregulated DEGs were enriched in primary immunodeficiency, cell adhesion molecules (CAMs), cytokine-cytokine receptor interaction, and hematopoietic cell lineages. CONCLUSIONS The findings from this bioinformatics network analysis study identified molecular mechanisms and the key hub genes that may contribute to synovial inflammation in patients with RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/fisiopatologia , Membrana Sinovial/fisiologia , Artrite Reumatoide/metabolismo , China , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Inflamação/metabolismo , Osteoartrite/genética , Mapeamento de Interação de Proteínas/métodos , Mapas de Interação de Proteínas/genética , Transdução de Sinais , Software , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Transcriptoma/genética
19.
Int Immunopharmacol ; 70: 428-434, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30856393

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory synovitis-based systemic disease characterized by invasive joint inflammation and synovial hyperplasia, which can lead to arthrentasis and defunctionalization. Previous research has shown that T cells, B cells, dendritic cells (DCs), and fibroblast-like synoviocytes (FLSs) play vital roles in the regulation of RA. Both T follicular helper (Tfh) cells and helper T (Th) 17 cells play immunomodulatory roles in RA. Moreover, interleukin-23 (IL-23), and IL-17 are vital to the pathogenesis of RA. T cells behave as a hub, in that B cells, DCs, and FLSs can interact with T cells to inhibit their activation and interfere with the process of RA. T cells cooperate with B cells, DCs, and FLSs to maintain the stability of the immune system under physiological conditions. However, under pathological conditions, the balance is disrupted, and the interaction of T cells with other cells may intensify disease progression. This review focuses on the interaction of T cells with B cells, DCs, and FLSs in different tissues and organs of RA patients and animal models, and highlight that the interplay between immune cells may underline the unique function of T cells and the application prospect of targeting T cell treatment for RA.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Células Dendríticas/imunologia , Fibroblastos/imunologia , Imunoterapia Adotiva/tendências , Sinoviócitos/imunologia , Linfócitos T/imunologia , Animais , Comunicação Celular , Modelos Animais de Doenças , Humanos , Membrana Sinovial/imunologia , Linfócitos T/transplante
20.
Int J Mol Sci ; 20(6)2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871134

RESUMO

The interleukin (IL)-1 family of cytokines is composed of 11 members, including the most recently discovered IL-36α, ß, γ, IL-37, and IL-38. Similar to IL-1, IL-36 cytokines are initiators and amplifiers of inflammation, whereas both IL-37 and IL-38 display anti-inflammatory activities. A few studies have outlined the role played by these cytokines in several inflammatory diseases. For instance, IL-36 agonists seem to be relevant for the pathogenesis of skin psoriasis whereas, despite being expressed within the synovial tissue, their silencing or overexpression do not critically influence the course of arthritis in mice. In this review, we will focus on the state of the art of the molecular features and biological roles of IL-36, IL-37, and IL-38 in representative skin- and joint-related inflammatory diseases, namely psoriasis, rheumatoid arthritis, and psoriatic arthritis. We will then offer an overview of the therapeutic potential of targeting the IL-36 axis in these diseases, either by blocking the proinflammatory agonists or enhancing the physiologic inhibitory feedback on the inflammation mediated by the antagonists IL-37 and IL-38.


Assuntos
Artrite Reumatoide/imunologia , Inflamação/imunologia , Interleucinas/imunologia , Articulações/imunologia , Pele/imunologia , Animais , Artrite Psoriásica/imunologia , Humanos , Psoríase/imunologia , Membrana Sinovial/imunologia
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