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1.
Immunology ; 159(1): 109-120, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606893

RESUMO

Serpins are evolutionarily conserved serine protease inhibitors that are widely distributed in animals, plants and microbes. In this study, we reported the cloning and functional characterizations of two novel serpin genes, HlSerpin-a and HlSerpin-b, from the hard tick Haemaphysalis longicornis of China. Recombinant HlSerpin-a and HlSerpin-b displayed protease inhibitory activities against multiple mammalian proteases. Similar to other tick serpins, HlSerpin-a and HlSerpin-b suppressed the expression of inflammatory cytokines such as TNF-α, interleukin (IL)-6 and IL-1ß from lipopolysaccharide-stimulated mouse bone-marrow-derived macrophages (BMDMs) or mouse bone-marrow-derived dendritic cells (BMDCs). The minimum active region (reaction centre loop) of HlSerpin-a, named SA-RCL, showed similar biological activities as HlSerpin-a in the protease inhibition and immune suppression assays. The immunosuppressive activities of full-length HlSerpin-a and SA-RCL are impaired in Cathepsin G or Cathepsin B knockout mouse macrophages, suggesting that the immunomodulation functions of SA and SA-RCL are dependent on their protease inhibitory activity. Finally, we showed that both full-length HlSerpins and SA-RCL can relieve the joint swelling and inflammatory response in collagen-induced mouse arthritis models. These results suggested that HlSerpin-a and HlSerpin-b are two functional arthropod serpins, and the minimal reactive peptide SA-RCL is a potential candidate for drug development against inflammatory diseases.


Assuntos
Artrite Experimental/prevenção & controle , Proteínas de Artrópodes/farmacologia , Células Dendríticas/efeitos dos fármacos , Imunossupressores/farmacologia , Ixodidae/metabolismo , Articulações/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Serpinas/farmacologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/isolamento & purificação , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunossupressores/isolamento & purificação , Ixodidae/genética , Articulações/imunologia , Articulações/metabolismo , Articulações/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Conformação Proteica , Células RAW 264.7 , Saliva/metabolismo , Serpinas/genética , Serpinas/isolamento & purificação , Relação Estrutura-Atividade
2.
Zhonghua Nei Ke Za Zhi ; 58(12): 911-914, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31775456

RESUMO

The purpose of this study was to explore the role and mechanism of transient receptor potential M(2) (TRPM(2)) in antigen-induced arthritis (AIA) mice. Twelve C57BL/6 mice and 12 TRPM(2) knockout mice were divided into 4 groups, includingwild type control group, wild type AIA group, TRPM(2) knockout control group and TRPM(2) knockout AIA group, with 6 mice in each group. Methylated bovine serum albumin (mBSA) was used to establish AIA mouse model. The degree of joint swelling and inflammatory cell infiltration were recorded, as well as synovial hyperplasia of the knee joints. Real-time quantitative polymerase chain reaction (PCR) was used to detect the expression of interleukin (IL)-6, IL-8, chemokine ligand 6 (CXCL-6) and tumor necrosis factor alpha (TNFα) mRNA in synovial cells of knee joints. The results showed that compared with the wild-type AIA group, the TRPM(2) knockout AIA group had more significant synovial proliferation and inflammatory cell infiltration in the synovial tissue.The neutrophil and macrophage counts rather than monocytes in the knee joints of TRPM(2) knockout AIA group were higher than those in wild-type AIA mice. The expression of IL-6, IL-8 and CXCL-6 mRNA were significantly increased in the knock out mice. In summary, TRPM(2) may inhibit inflammatory cytokines such as IL-6 and IL-8 in knee joints of AIA mice by reducing the infiltration of neutrophils and macrophages, the refore alleviates the manifestations of knee arthritis.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Quimiocina CXCL6/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Soroalbumina Bovina/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Antígenos/imunologia , Artrite Reumatoide/genética , Quimiocina CXCL6/genética , Interleucina-6/genética , Interleucina-8/genética , Articulação do Joelho/imunologia , Articulação do Joelho/patologia , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real , Membrana Sinovial , Fator de Necrose Tumoral alfa/genética
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.
Biol Pharm Bull ; 42(8): 1419-1422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366877

RESUMO

The pathogenic relationship of ulcerative colitis and rheumatoid arthritis is not known. Therefore, we examined dextran sodium sulfate (DSS)-induced colitis separately and in combination with a mouse arthritis model that mimics rheumatoid arthritis and evaluated the deterioration-related factors of each condition. Arthritis was induced in a collagen-induced arthritis mouse model using DBA/1JJmsSlc mice and ulcerative colitis was induced by the administration of drinking water containing 3.0% (w/v) DSS. The arthritis/DSS-treated mice developed worse colitis scores compared to that of the other groups of mice. The arthritis/DSS-treated mice did not demonstrate changes in hind foot volumes or in the concentration of matrix metalloproteinase-3 (MMP-3) in the plasma; however, plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α were increased. Our results showed that IL-6 and TNF-α may influence the deterioration effect of colitis in arthritic mice.


Assuntos
Artrite Experimental/imunologia , Colite Ulcerativa/imunologia , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangue , Animais , Artrite Experimental/sangue , Artrite Experimental/patologia , Colite Ulcerativa/sangue , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana , Edema/sangue , Edema/imunologia , Edema/patologia , Pé/patologia , Metaloproteinase 3 da Matriz/sangue , Camundongos Endogâmicos DBA
5.
Int J Mol Sci ; 20(13)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266174

RESUMO

It is incompletely understood how self-antigens become targets of humoral immunity in antibody-mediated autoimmune diseases. In this context, alarmins are discussed as an important level of regulation. Alarmins are recognized by various receptors, such as receptor for advanced glycation end products (RAGE). As RAGE is upregulated under inflammatory conditions, strongly binds nucleic acids and mediates pro-inflammatory responses upon alarmin recognition, our aim was to examine its contribution to immune complex-mediated autoimmune diseases. This question was addressed employing RAGE-/- animals in murine models of pristane-induced lupus, collagen-induced, and serum-transfer arthritis. Autoantibodies were assessed by enzyme-linked immunosorbent assay, renal disease by quantification of proteinuria and histology, arthritis by scoring joint inflammation. The associated immune status was determined by flow cytometry. In both disease entities, we detected tendentiously decreased autoantibody levels in RAGE-/- mice, however no differences in clinical outcome. In accordance with autoantibody levels, a subgroup of the RAGE-/- animals showed a decrease in plasma cells, and germinal center B cells and an increase in follicular B cells. Based on our results, we suggest that RAGE deficiency alone does not significantly affect antibody-mediated autoimmunity. RAGE may rather exert its effects along with other receptors linking environmental factors to auto-reactive immune responses.


Assuntos
Artrite Experimental/imunologia , Autoanticorpos/metabolismo , Nefrite Lúpica/imunologia , Receptor para Produtos Finais de Glicação Avançada/deficiência , Animais , Artrite Experimental/genética , Autoanticorpos/sangue , Linfócitos B/imunologia , Colágeno/efeitos adversos , Modelos Animais de Doenças , Centro Germinativo/imunologia , Nefrite Lúpica/genética , Camundongos , Receptor para Produtos Finais de Glicação Avançada/imunologia , Terpenos/efeitos adversos
6.
J Immunol Res ; 2019: 1982570, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355296

RESUMO

Dendritic cells (DCs) have the ability to induce tolerance or inflammation in response to self-antigens, which makes them fundamental players in autoimmunity. In this regard, immunogenic DCs produce IL-12 and IL-23 favouring the acquisition of Th1 and Th17 inflammatory phenotypes, respectively, by autoreactive CD4+ T-cells, thus promoting autoimmunity. Conversely, tolerogenic DCs produce IL-10 and TGF-ß, inducing the generation of CD4+ T-cells with suppressive activity (Treg), which promote tolerance to self-constituents. Previous studies have shown that STAT3 signalling in DCs attenuates the production of proinflammatory cytokines, whilst NF-κB activation promotes it. In this study, we aimed to generate DCs displaying strong and constitutive tolerogenic profile to be used as immunotherapy in autoimmunity. To this end, we transduced bone marrow-derived DCs with lentiviral particles codifying for a constitutively active version of STAT3 (constitutively active STAT3 (STAT3ca)) or with a constitutive repressor of NF-κB (IκBα superrepressor (IκBαSR)), and their therapeutic potential was evaluated in a mouse model of arthritis induced by collagen (CIA). Our results show that STAT3ca transduction favoured the production of the anti-inflammatory mediator IL-10, whereas IκBαSR transduction attenuated the expression of the proinflammatory cytokine IL-23 in DCs. Moreover, both STAT3ca-transduced and IκBαSR-transduced DCs separately exerted a mild but significant therapeutic effect reducing the severity of CIA development. Furthermore, when DCs were transduced with both STAT3ca and IκBαSR together, they reduced CIA manifestation significantly stronger than when transduced with only STAT3ca or IκBαSR separately. These results show STAT3 and NF-κB as two important and complementary regulators of the tolerogenic behaviour of DCs, which should be considered as molecular targets in the design of DC-based suppressive immunotherapies for the treatment of autoimmune disorders.


Assuntos
Artrite Experimental/terapia , Células Dendríticas/transplante , Tolerância Imunológica/imunologia , NF-kappa B/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Inflamação , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Masculino , Camundongos , Fator de Transcrição STAT3/metabolismo , Células Th1/imunologia , Células Th17/imunologia
7.
Mol Immunol ; 112: 188-197, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176198

RESUMO

Rheumatoid arthritis (RA) is a chronic, systemic, synovitis-based inflammatory disease with unknown etiology. Neutrophils play important roles in the pathogenesis of RA. Apoptosis and NETosis of neutrophils are two major mechanisms of programmed cell death that differ in their morphological characteristics and effects on the immune system. In rheumatoid arthritis, delayed neutrophil apoptosis amplifies the inflammatory response; and massive release of NETs and their components may cause tissue damage and provide self-antigens. Emodin is a natural anthraquinone derivative that occurs in many widely used Chinese medicinal herbs. In this study, we evaluated the effect of emodin on a murine adjuvant-induced arthritis (AA) model of RA in vivo and on neutrophil apoptosis and NETosis in vitro. Our results show that emodin alleviated AA by reducing neutrophil infiltration and proinflammatory cytokine (interleukin-6, interferon-gamma and tumor necrosis factor-α) release. Emodin promoted apoptosis and inhibited autophagy and NETosis in neutrophils. These findings indicate that emodin represents a potential therapeutic agent for RA.


Assuntos
Apoptose/imunologia , Artrite Reumatoide/imunologia , Emodina/imunologia , Armadilhas Extracelulares/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Animais , Artrite Experimental/imunologia , Autoantígenos/imunologia , Autofagia/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/imunologia
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.
Int J Rheum Dis ; 22(7): 1255-1262, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31062502

RESUMO

AIM: Cumulative evidence has revealed that tolerogenic dendritic cells (tolDC) could relieve inflammation reactions in various autoimmune diseases. This study investigated the potential therapeutic application of vasoactive intestinal peptide (VIP)-induced tolDC (VIP-DC) on arthritis using collagen-induced arthritis (CIA) mice. METHODS: Bone marrow cells were differentiated into dendritic cells (DC) using granulocyte macrophage colony-stimulating factor and interleukin (IL)-4. tolDC were induced by either VIP or Bay 11-7082 in vitro. Immunophenotypes and cytokine production of VIP-DC and Bay-DC were detected by fluorescence-activated cell sorting and enzyme-linked immunosorbent assay, respectively. Bay-DC, VIP-DC and untreated DC were ip administrated to CIA mice on day 40 when arthritis was onset. The treatment effects on arthritic and pathological changes, including synovial hyperplasia, pannus formation, inflammation and bone erosion, were assessed. RESULTS: VIP-DC (40 ng/mL) and Bay-DC (0.5 µg/mL) had a lower level of major histocompatibility complex II, CD40 and CD86 expression, reduced γ-interferon and increased IL-4 production (P < 0.05 or 0.01), compared with untreated DC. The administration of VIP-DC and Bay-DC decreased the arthritis score clinically at the end of the therapy. Pathological assessments showed that bone erosion and inflammation were alleviated in the VIP-DC group compared with those in the untreated DC group (P < 0.05 and P < 0.01, respectively). CONCLUSION: VIP-DC showed reduced immunogenicity and enhanced anti-inflammatory cytokine production. Both VIP-DC and Bay-DC could ameliorate arthritis in CIA mice clinically. VIP-DC were not inferior to Bay 11-7082-induced tolDC but may exert a better preventive effect on bone destruction.


Assuntos
Artrite Experimental/prevenção & controle , Colágeno , Células Dendríticas/transplante , Tolerância Imunológica , Articulações/imunologia , Peptídeo Intestinal Vasoativo/imunologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD40/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon gama/metabolismo , Interleucina-4/metabolismo , Articulações/metabolismo , Articulações/patologia , Masculino , Camundongos Endogâmicos DBA , Fenótipo
10.
Biomed Pharmacother ; 115: 108909, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31071508

RESUMO

Ginsenoside metabolite compound-K (C-K), which is an active metabolite of ginsenoside in vivo, can produce anti-inflammatory affects by activating glucocorticoid receptors (GRs) to inhibit the expression of ß-arrestin2. Studies have shown that C-K can inhibit the function of immune cells including macrophage polarization and phagocytosis. However, the mechanism by which C-K regulates macrophage polarization is currently unclear. Toll-like receptors (TLRs) are the pattern recognition receptors on the membrane of immune cells, with TLR4 being especially important in polarization of macrophages. The Gαi-mediated activation of nuclear factor-κB (NF-κB) by TLR4 promotes inflammation and phagocytosis in macrophages by increasing the proportion of type I phenotypic macrophages (M1). Whether C-K inhibits the signal transduction of TLR4-Gαi-NF-κB and how that effects macrophage polarization regulation in murine models of RA is not reported. The coupling of G proteins with receptors is regulated by ß-arrestin2, but it has been unclear whether C-K modulates the TLR4 interaction with G proteins by inhibiting the expression of ß-arrestin2. To explore these questions, the collagen-induced arthritis (CIA) mouse model was employed, and mice were treated with C-K (112 mg/kg/day). The results depict that C-K treatment inhibits macrophage phagocytosis and reduces the proportion of M1. C-K decreases the overexpressed ß-arrestin2, Gαi, TLR4 and NF-κB in macrophages of CIA mice, while increasing the expression of Gαs. Furthermore, C-K promotes TLR4-Gαs coupling and inhibits TLR4-Gαi coupling through ß-arrestin2 regulation in macrophages, leading to a decrease in the proportion of M1 to M2 macrophages and improved outcomes in CIA mice.


Assuntos
Artrite Experimental/tratamento farmacológico , Ginsenosídeos/uso terapêutico , Macrófagos Peritoneais/efeitos dos fármacos , beta-Arrestina 2/antagonistas & inibidores , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Células Cultivadas , Citocinas/sangue , Articulações do Pé/efeitos dos fármacos , Articulações do Pé/imunologia , Articulações do Pé/patologia , Macrófagos Peritoneais/imunologia , Camundongos Endogâmicos DBA , Fagocitose/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/imunologia , Timo/efeitos dos fármacos , Timo/imunologia , beta-Arrestina 2/genética
11.
Clin Exp Rheumatol ; 37(6): 983-993, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31074720

RESUMO

OBJECTIVES: In this study, we used hypercholesterolaemic apolipoprotein E-deficient (Apoe-/-) mice to investigate LDL/oxLDL effect on synovial inflammation and cartilage destruction during antigen-induced arthritis (AIA). Further, as macrophage FcγRs are crucial to immune complex-mediated AIA, we investigated in vitro the effects of high cholesterol levels on the expression of FcγRs on macrophages. METHODS: AIA was induced by intra-articular injection of mBSA into knee joints of immunised Apoe-/- and wild type (WT) control mice. Joint swelling was measured by uptake of 99mTc pertechnetate (99mTc). Joint inflammation and cartilage destruction were assessed by histology. Anti-mBSA IgGs were measured by ELISA and specific T-cell response by lymphocyte stimulation test. Upon oxLDL stimulation of WT macrophages, protein levels of FcγRs were measured by flow cytometry. RESULTS: Local induction of AIA resulted in less joint swelling, synovial infiltrate and exudate in the joint cavity in Apoe-/- mice compared to WT controls, even though both their humoral and adaptive immune response were comparable. Whereas Apoe deficiency alone did not affect macrophage expression of FcγRs, oxLDL sharply reduced the protein levels of activating FcγRs, crucial in mediating cartilage damage. In agreement with the reduced inflammation in Apoe-/- mice, we observed decreased MMP activity and destruction in the articular cartilage. CONCLUSIONS: Taken together, our findings suggest that high levels of LDL/oxLDL during inflammation, dampen the initiation and chronicity of joint inflammation and cartilage destruction in AIA by regulating macrophage FcγR expression.


Assuntos
Artrite Experimental , Cartilagem Articular , LDL-Colesterol/sangue , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Modelos Animais de Doenças , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de IgG
12.
J Pharmacol Exp Ther ; 370(2): 182-196, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31085699

RESUMO

Ectoenzyme CD38 is increased on lymphocytes in response to an antigenic challenge and it is hypothesized that targeting these activated lymphocytes could ameliorate pathologic activities in autoimmune diseases. The cynomolgus monkey is an appropriate model for assessing potential effects of targeting CD38 in humans because these species exhibit similar expression profiles. TAK-079 is a human monoclonal antibody (IgG1 λ ) that binds to CD38 and lyses bound cells by complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. TAK-079 binds to monkey CD38 with an affinity at EC50 4.5 nM, and the potential activity of TAK-079 was investigated in a monkey collagen-induced arthritis model of autoimmune disease. Prophylactic administration of TAK-079 (3 mg/kg i.v. weekly) was well tolerated and prevented arthritis development compared with vehicle-treated control animals, which exhibited progressive disease with radiographic damage and worsening clinical scores over the study course. Therapeutic treatment of arthritic monkeys with TAK-079 (3 mg/kg i.v. weekly) was also well tolerated and reduced disease progression and symptoms. Arthritis scores and joint swelling were significantly lower than the vehicle control, accompanied by decreases in blood levels of C-reactive protein, alkaline phosphatase, and natural killer, B, and T cells. Histopathology, morphometry, and radiology revealed significantly less joint damage in animals exposed prophylactically to TAK-079 treatment compared with vehicle-treated animals and significantly less damage in animals treated therapeutically with TAK-079 or dexamethasone (0.1 mg/kg oral gavage daily), illustrating potential disease-modifying activity. In conclusion, these data indicate that depletion of CD38-expressing cells could be a therapeutic mechanism for treating autoimmune diseases. SIGNIFICANCE STATEMENT: This study demonstrates that targeting CD38-expressing leukocytes with a cytolytic antibody can ameliorate autoimmune disease in cynomolgus monkeys. The study gives a unique perspective into this therapeutic strategy because the three other anti-CD38 cytolytic antibodies in clinical development (daratumumab, isatuximab, and MOR202) cannot be tested in similar models because they do not crossreact with CD38 expressed by new world primates.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Anticorpos Monoclonais/imunologia , Artrite Experimental/imunologia , Linfócitos B/metabolismo , Regulação da Expressão Gênica/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos T/metabolismo , ADP-Ribosil Ciclase 1/imunologia , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Linfócitos B/imunologia , Células CHO , Cricetulus , Progressão da Doença , Células Matadoras Naturais/imunologia , Macaca fascicularis , Linfócitos T/imunologia
13.
Int Immunopharmacol ; 72: 292-300, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31005039

RESUMO

Curcumin is a natural herbal product that has been popularly used to treat autoimmune diseases in China; however, its effects on rheumatoid arthritis and its mechanism are not clear. The main purposes of this study are to explore the therapeutic effects of curcumin on collagen-induced arthritis (CIA) rats and the pharmacological mechanism. In the present study, CIA rats were established by injecting bovine type II collagen. Curcumin and methotrexate were then orally administered daily, and the swelling degree of the hind limb joints was scored every two days. Histopathological changes were observed by hematoxylin-eosin staining. The levels of cytokines (TNF-α, IL-1ß, IL-17 and TGF-ß) were detected by radioimmunoassay, while the expression of IκBα and COX-2 was detected by Western blot. In addition, cell viability was detected by CCK-8 assay, and the effect of curcumin on macrophage apoptosis was detected by flow cytometry and TUNEL assay. The results indicated that in vivo curcumin attenuated the degree of joint swelling of rats and the further development of joint histopathology. Moreover, it downregulated the levels of cytokines. In vitro curcumin inhibited the degradation of IκBα and reduced the production of COX-2 in LPS-induced inflammatory RAW264.7 cells. Importantly, curcumin significantly induced macrophage apoptosis. In conclusion, in this study, we have demonstrated that curcumin exerts therapeutic effects on arthritis in CIA rats and has a strong pharmacological activity on reducing the inflammatory response in macrophages. Its mechanism may be related to the inhibition of the NF-κB signaling pathway and the promotion of macrophage apoptosis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Curcumina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Artrite Experimental/imunologia , Artrite Experimental/patologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/imunologia , Articulações/efeitos dos fármacos , Articulações/imunologia , Articulações/patologia , Masculino , Camundongos , Células RAW 264.7 , Ratos Sprague-Dawley
14.
Biol Pharm Bull ; 42(7): 1172-1178, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31019160

RESUMO

To study the role of asarinin on collagen-induced arthritis (CIA) and its treatment mechanism on dendritic cells (DCs) and T cells. Before the onset of arthritis, asarinin were given orally to CIA mouse. Macroscopic scoring and micrometer caliper measurement were used to assess arthritis. The occurrence of cartilage destruction and bone erosion were assessed by histology of knee. Sandwich enzyme-linked immunosorbent assay (ELISA) and PCR were used to assess the level of cytokines in hindpaw and arthritic joint. The CD11c MicroBeads were employed to isolate CD11c+ cells from the spleen. Quantitative PCR was used to determine DCs surface molecules of spleen. Macroscopic score and the frequency of arthritis were inhibited by asarinin. Swelling of hindpaws, inflammatory cell infiltration in the synovium, cartilage destruction, and bone erosion were delayed with asarinin. Asarinin treatment suppressed the expression of T helper type 1 (Th1) cytokines and increased the levels of Th2 cytokines (interleukin (IL)-10), transforming growth factor (TGF)-ß and Foxp3 in the synovium and hindpaw, however T-bet mRNA levels in synovium decreased. Lower expression of toll-like receptor 9 (TLR9) and nuclear factor-kappaB (NF-κB) were found in DCs after asarinin treatment. There was no difference in the expression of intercellular cell adhesion molecule-1(ICAM-1), OX40-L, and 4-1BBL in spleen DCs between the asarinin group and model control group. Asarinin can treat CIA. TLR9/NF-κB pathway may be involved in the asarinin treatment of CIA by skewing the balance of Th1/Th2/regulatory T (Treg) to a Th2 type.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Dioxóis/uso terapêutico , Lignanas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/imunologia , Artrite Experimental/patologia , Citocinas/imunologia , Dioxóis/farmacologia , Regulação para Baixo/efeitos dos fármacos , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/patologia , Lignanas/farmacologia , Masculino , Camundongos Endogâmicos DBA , NF-kappa B/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Receptor Toll-Like 9/imunologia
15.
Biomolecules ; 9(4)2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30970641

RESUMO

Chronic inflammatory autoimmune disorders are systemic diseases with increasing incidence and still lack a cure. More recently, attention has been placed in understanding gastrointestinal (GI) dysbiosis and, although important progress has been made in this area, it is currently unclear to what extent microbiome manipulation can be used in the treatment of autoimmune disorders. Via the use of appropriate models, rheumatoid arthritis (RA), a well-known exemplar of such pathologies, can be exploited to shed light on the currently overlooked effects of existing therapies on the GI microbiome. In this direction, we here explore the crosstalk between the GI microbiome and the host immunity in model arthritis (collagen induced arthritis, CIA). By exploiting omics from samples of limited invasiveness (blood and stools), we assess the host-microbiome responses to standard therapy (methotrexate, MTX) combined with mechanical subcutaneous stimulation (MS) and to mechanical stimulation alone. When MS is involved, results reveal the sphingolipid metabolism as the trait d'union among known hallmarks of (model) RA, namely: Imbalance in the S1P-S1PR1 axis, expansion of Prevotella sp., and invariant Natural Killer T (iNKT)-penia, thus offering the base of a rationale to mechanically modulate this pathway as a therapeutic target in RA.


Assuntos
Artrite Experimental/microbiologia , Microbioma Gastrointestinal , Interações Hospedeiro-Patógeno , Esfingolipídeos/metabolismo , Animais , Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Feminino , Células Matadoras Naturais/imunologia , Metotrexato/uso terapêutico , Prevotella/patogenicidade , Ratos , Ratos Wistar , Estresse Mecânico
16.
J Immunol Res ; 2019: 2641098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30937315

RESUMO

The inflammatory and autoimmune events preceding clinical symptoms in rheumatoid arthritis (RA) and other autoimmune diseases are difficult to study in human patients. Therefore, animal models that share immunologic and clinical features with human RA, such as pristane-induced arthritis (PIA), are valuable tools for assessing the primordial events related to arthritis susceptibility. PIA-resistant HIII and susceptible LIII mice were injected i.p. with pristane, and peritoneal lavage fluid was harvested in the early (7 days) and late (35 days) preclinical phases of PIA. Chemokine and cytokine levels were measured in lavage supernatant with ELISA, peritoneal inflammatory leukocytes were immunophenotyped by flow cytometry, and gene expression was determined by qRT-PCR. Leukocyte recruitment was quantitatively and qualitatively divergent in the peritoneum of HIII and LIII mice, with an early increase of CC chemokines (CCL2/CCL3/CCL5/CCL12/CCL22) in the susceptible LIII strain. Also, cytokines such as IL-12p40, IL-23, and IL-18 were elevated in LIII mice while IL-6 was increased in HIII animals. The results show that an early peritoneal CC chemokine response is an important feature of arthritis susceptibility and defines potential biomarkers in this model.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Quimiocinas CC/imunologia , Inflamação , Peritônio/imunologia , Animais , Artrite Experimental/induzido quimicamente , Biomarcadores , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Interleucina-6/imunologia , Masculino , Camundongos , Fenótipo , Terpenos/administração & dosagem
17.
Ann Rheum Dis ; 78(6): 787-795, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30928902

RESUMO

OBJECTIVES: The mechanisms driving onset of joint inflammation in arthritides such as rheumatoid arthritis and spondyloarthritis and the conversion to disease chronicity are poorly understood. We hypothesised mechanostrain could play an instrumental role herein by engaging local and/or systemic pathways, thereby attenuating disease course and outcome. METHODS: The development of collagen antibody-induced arthritis (CAIA) in C57BL/6 mice was evaluated both clinically and histologically under different loading regimens: control, voluntary running or hindpaw unloading. Bone surface porosity was quantified by high-resolution µ-CT. Gene expression analyses were conducted by microarrays and qPCR on microdissected entheses, murine and human synovial tissues (both normal and inflamed). Serum cytokines and chemokines were measured by ELISA. The influence of complement activation and T regulatory (Treg) cell function on the induction and resolution phase of disease was studied by respectively pharmacological modulation and conditional Treg depletion. RESULTS: Voluntary running strongly impacts the course of arthritis by impairing the resolution phase of CAIA, leading to more persistent inflammation and bone surface porosity. Mechanical strain induced local complement activation, increased danger-associated molecular pattern expression, activating Fcγ receptors as well as changes in fibroblast phenotype. Interestingly, complement C5a receptor blockade inhibited the enhanced joint pathology caused by voluntary running. Moreover, Treg depletion led to a loss of disease resolution in CAIA mice, which was not observed under voluntary running conditions. CONCLUSIONS: Running promotes onset and chronicity of arthritis by local upregulation of complement activators and hampering regulatory T cell feedback loops.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Ativação do Complemento/fisiologia , Corrida/fisiologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Animais , Artrite Experimental/fisiopatologia , Artrite Reumatoide/fisiopatologia , Doença Crônica , Progressão da Doença , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Mecanotransdução Celular/imunologia , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Properdina/biossíntese , Estresse Mecânico , Membrana Sinovial/metabolismo
18.
J Ethnopharmacol ; 238: 111861, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30954617

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Wang-bi tablet (WB) consists of 17 traditional Chinese medicines and has been used for treating rheumatoid arthritis (RA) in China for many years, however, its pharmacologic mechanism is not clear. AIM OF STUDY: The aim of this study was to investigate the therapeutic effect of WB on collagen-induced mouse arthritis and explored the underlying mechanism. MATERIALS AND METHODS: DBA/1 mice were used to establish a type II collagen-induced arthritis (CIA) model. From the day of arthritis onset, mice were treated daily by gavage with either total glucosides of paeony (TGP, 0.37  g/kg/d) or WB at a lower (1.11  g/kg/d, WBL) or higher dose of (3.33  g/kg/d, WBH) for 8 weeks. The severity of arthritis, levels of cytokines and the activation of signaling pathways were determined. RESULTS: Our results revealed that WB treatment effectively alleviated inflammatory symptoms and prevented bone erosions and joint destructions. It obviously decreased the serum concentration of pro-inflammatory cytokines TNF-α, IL-6 and IL-17α, while increased the concentration of anti-inflammatory cytokine IL-10. Interestingly, the proportion of splenic Treg cells were increased significantly. In vitro experiments showed that WB inhibited the differentiation of osteoclasts. Consistently, the mRNA levels of tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CtsK), and the activation of NF-κB and JAK-STAT3 signaling pathways in the paws of CIA mice were inhibited by WB treatment. On the other hand, up-regulation of osteogenic genes Runx2, Osterix mRNA, and activation of Wnt/ß-catenin signaling pathway along with a decreased receptor activator of nuclear factor κB ligand (RANKL) expression were found in WB treated mice. CONCLUSION: Our results suggest that the therapeutic effect of Wang-bi tablet could be attributed to its inhibitory activity on NF-κB and STAT3 signaling pathway-mediated osteoclast differentiation, and its enhancement on Wnt/ß-catenin signaling pathway-mediated osteoblast functions.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Citocinas/imunologia , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Medicina Tradicional Chinesa , Camundongos Endogâmicos DBA , NF-kappa B/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Ligante RANK/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Via de Sinalização Wnt/efeitos dos fármacos
19.
Nat Commun ; 10(1): 1554, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952846

RESUMO

The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent rise of allergic, autoimmune and metabolic disorders. Certainly, gastrointestinal helminths can protect against gut and lung mucosa inflammatory conditions by modulating the microbiome and suppressing the chronic inflammation associated with dysbiosis. Here, we employ ES-62, an immunomodulator secreted by tissue-dwelling Acanthocheilonema viteae to show that helminth-modulation of the gut microbiome does not require live infection with gastrointestinal-based worms nor is protection restricted to mucosal diseases. Specifically, subcutaneous administration of this defined immunomodulator affords protection against joint disease in collagen-induced arthritis, a mouse model of rheumatoid arthritis, which is associated with normalisation of gut microbiota and prevention of loss of intestinal barrier integrity.


Assuntos
Antibacterianos/farmacologia , Artrite Experimental/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Proteínas de Helminto/uso terapêutico , Animais , Artrite Experimental/imunologia , Proteínas de Helminto/farmacologia , Imunomodulação , Masculino , Camundongos
20.
Arch Immunol Ther Exp (Warsz) ; 67(3): 153-160, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30874838

RESUMO

Rheumatoid arthritis (RA) is a common autoimmune disease which impacts a large number of patients worldwide, and new drugs are required for lower the disease burden. Theaflavin-3, 3'-digallate (TFDG) is polyphenol exhibiting inhibition on inflammatory factors. This study aimed to explore the attenuation of TFDG on RA. The collagen-induced arthritis (CIA) mouse model was established and administered with TFDG. The arthritis score and incidence was recorded to assess the amelioration of TFDG on arthritis. Histopathological change of the mouse joint tissues was evaluated by haemotoxylin and eosin staining. The expression of pro-inflammatory mediators including interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 was quantified by ELISA. The activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways in the synovium were determined by Western blotting. In comparison with the control, administration of TFDG significantly reduced arthritis score and incidence in the CIA mouse model. TFDG significantly suppressed the expression of IL-1ß, TNF-α, and IL-6, as well as the levels of MMP-1, MMP-2, and MMP-3 in the synovium. TFDG also showed remarkable inhibition on the activation of NF-κB and the phosphorylation of P38, JNK2, and ERK. This study puts up evidence that TFDG exerts protection on RA via inhibiting the activation of NF-κB- and MAPK-signaling pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Biflavonoides/farmacologia , Catequina/farmacologia , Ácido Gálico/análogos & derivados , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Biflavonoides/uso terapêutico , Catequina/uso terapêutico , Colágeno/administração & dosagem , Colágeno/imunologia , Avaliação Pré-Clínica de Medicamentos , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Humanos , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Articulações/efeitos dos fármacos , Articulações/imunologia , Articulações/patologia , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/imunologia , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
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