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1.
Biochim Biophys Acta Mol Basis Dis ; 1866(1): 165554, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513833

RESUMO

Activation of interferon (IFN)-I signaling in B cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Recent studies have shown that myeloid-derived suppressor cells (MDSCs) significantly expand in SLE patients and lupus-prone MRL/lpr mice and contribute to the pathogenesis of SLE. However, the role of SLE-derived MDSCs in regulating IFN-I signaling activation of B cells remains unknown. Here, we demonstrate that expansions of MDSCs, including granulocyte (G)-MDSCs and monocytic (M)-MDSCs, during the progression of SLE were correlated with the IFN-I signature of B cells. Interestingly, G-MDSCs from MRL/lpr mice, but not M-MDSCs, could significantly promote IFN-I signaling activation of B cells and contribute to the pathogenesis of SLE. Mechanistically, we identified that the long non-coding RNA NEAT1 was over-expressed in G-MDSCs from MRL/lpr mice and could induce the promotion of G-MDSCs on IFN-I signaling activation of B cells through B cell-activating factor (BAFF) secretion. Importantly, NEAT1 deficiency significantly attenuated the lupus symptoms in pristane-induced lupus mice. In addition, there was a positive correlation between NEAT1 and BAFF with the IFN signature in SLE patients. In conclusion, G-MDSCs may contribute to the IFN signature in SLE B cells through the NEAT1-BAFF axis, highlighting G-MDSCs as a potential therapeutic target to treat SLE.

2.
Immunology ; 157(3): 257-267, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31120548

RESUMO

Asthma is a chronic inflammatory disease that involves a variety of cytokines and cells. Interleukin-16 (IL-16) is highly expressed during allergic airway inflammation and is involved in its development. However, its specific mechanism of action remains unclear. In the present study, we used an animal model of ovalbumin (OVA)-induced allergic asthma with mice harboring an IL-16 gene deletion to investigate the role of this cytokine in asthma, in addition to its underlying mechanism. Increased IL-16 expression was observed during OVA-induced asthma in C57BL/6J mice. However, when OVA was used to induce asthma in IL-16-/- mice, a diminished inflammatory reaction, decreased bronchoalveolar lavage fluid (BALF) eosinophil numbers, and the suppression of OVA-specific IgE levels in the serum and BALF were observed. The results also demonstrated decreased levels of T helper type 2 (Th2) and Th17 cytokines upon OVA-induced asthma in IL-16-/- mice. Hence, we confirmed that IL-16 enhances the lung allergic inflammatory response and suggest a mechanism possibly associated with the up-regulation of IgE and the promotion of Th2 and Th17 cytokine production. This work explored the mechanism underlying the regulation of IL-16 in asthma and provides a new target for the clinical treatment of asthma.

3.
Front Immunol ; 10: 215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809230

RESUMO

Dysregulation of macrophage has been demonstrated to contribute to aberrant immune responses and inflammatory diseases. CD11b, expressed on macrophages, plays a critical role in regulating pathogen recognition, phagocytosis, and cell survival. In the present study, we explored the effect of leukadherin-1 (LA1), an agonist of CD11b, on regulating LPS-induced pro-inflammatory response in macrophages and endotoxic shock. Intriguingly, we found that LA1 could significantly reduce mortalities of mice and alleviated pathological injury of liver and lung in endotoxic shock. In vivo studies showed that LA1-induced activation of CD11b significantly inhibited the LPS-induced pro-inflammatory response in macrophages of mice. Moreover, LA1-induced activation of CD11b significantly inhibited LPS/IFN-γ-induced pro-inflammatory response in macrophages by inhibiting MAPKs and NF-κB signaling pathways in vitro. Furthermore, the mice injected with LA1-treated BMDMs showed fewer pathological lesions than those injected with vehicle-treated BMDMs in endotoxic shock. In addition, we found that activation of TLR4 by LPS could endocytose CD11b and activation of CD11b by LA1 could endocytose TLR4 in vitro and in vivo, subsequently blocking the binding of LPS with TLR4. Based on these findings, we concluded that LA1-induced activation of CD11b negatively regulates LPS-induced pro-inflammatory response in macrophages and subsequently protects mice from endotoxin shock by partially blocking LPS-TLR4 interaction. Our study provides a new insight into the role of CD11b in the pathogenesis of inflammatory diseases.

4.
Immunology ; 157(1): 13-20, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30681737

RESUMO

Interleukin-35 (IL-35) is a recently identified heterodimeric cytokine in the IL-12 family. It consists of an IL-12 subunit α chain (P35) and IL-27 subunit Epstein-Barr virus-induced gene 3 (EBI3) ß chain. Unlike the other IL-12 family members, it signals through four unconventional receptors: IL-12Rß2-IL-27Rα, IL-12Rß2-IL-12Rß2, IL-12Rß2-GP130, and GP130-GP130. Interleukin-35 signaling is mainly carried out through the signal transducer and activator of transcription family of proteins. It is secreted not only by regulatory T (Treg) cells, but also by CD8+ Treg cells, activated dendritic cells and regulatory B cells. It exhibits immunosuppressive functions distinct from those of other members of the IL-12 family; these are mediated primarily by the inhibition of T helper type 17 cell differentiation and promotion of Treg cell proliferation. Interleukin-35 plays a critical role in several immune-associated diseases, such as autoimmune diseases and viral and bacterial infections, as well as in tumors. In this review, we summarize the structure and function of IL-35, describe its role in immune-related disorders, and discuss the mechanisms by which it regulates the development and progression of diseases, including inflammatory bowel disease, collagen-induced arthritis, allergic airway disease, hepatitis, and tumors. The recent research on IL-35, combined with improved techniques of studying receptors and signal transduction pathways, allows for consideration of IL-35 as a novel immunotherapy target.


Assuntos
Doenças do Sistema Imunitário/metabolismo , Imunoterapia/métodos , Subunidade p35 da Interleucina-12/metabolismo , Interleucinas/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Autoimunidade , Humanos , Subunidade p35 da Interleucina-12/genética , Interleucinas/genética , Ativação Linfocitária , Antígenos de Histocompatibilidade Menor/genética , Transdução de Sinais
5.
Biochim Biophys Acta Mol Basis Dis ; 1865(3): 535-546, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30557700

RESUMO

Myeloid-derived suppressor cells (MDSCs) play an immunosuppressive role in the pathogenesis of inflammatory diseases. CD180, a TLR-like protein, can regulate the proliferation and activation of immune cells. However, the roles of CD180 in regulating the accumulation and function of MDSCs have not been investigated. Here, we found that, compared with non-treated controls, the expression of CD180 was significantly elevated in MDSCs, especially granulocytic MDSCs (G-MDSCs), from mice challenged with lipopolysaccharide (LPS). Ligation of CD180 by the anti-CD180 antibody not only blocked the expansion of MDSCs by preventing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), but also reduced the immunosuppressive activity of MDSCs on M1 macrophage polarization through inhibition of Arg-1 expression in vitro. In vivo studies showed that injection of anti-CD180 antibody significantly aggravated pathological lesions in mice challenged with LPS. Furthermore, injection of anti-CD180 antibody inhibited the accumulation of G-MDSCs in mice challenged with LPS and reduced the immunosuppressive activity of G-MDSCs on M1 macrophage polarization. Based on these findings, we conclude that ligation of CD180 contributes to the pathogenesis of endotoxic shock by inhibiting the accumulation and immunosuppressive activity of G-MDSCs, thus providing insight into the function of CD180 in inflammatory diseases.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Células Supressoras Mieloides/imunologia , Fator de Transcrição STAT3/fisiologia , Choque Séptico/induzido quimicamente , Choque Séptico/imunologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/efeitos dos fármacos , Ligação Proteica , Choque Séptico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 34(11): 961-968, 2018 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30591103

RESUMO

Objective To study the effect of CD11b agonist leukadherin-1 (LA1) on the aggregation and immunosuppressive function of myeloid-derived suppressor cells (MDSCs) and its therapeutic effect on the condition of endotoxic shock mice. Methods The percentages of MDSCs , granulocytic myeloid-derived suppressor cells(G-MDSCs)and monocytic myeloid-derived suppressor cells(M-MDSCs)in spleen were detected by flow cytometry, after C57BL/6 female mice were injected of LA1 to activate through abdominal cavity for 12 hours and 48 hours. MDSCs were induced from the femur and tibia of C57BL/6 female mice in vitro. The expression levels of immunosuppressive related factors, such as interleukin 10 (IL-10), NADPH oxidase 1 (NOX1) and inducible nitric oxide synthase (iNOS) , were detected by real time quantitative PCR. C57BL/6 female mice were randomly divided into PBS group, LA1 group, PBS combined LPS group and LA1 combined LPS group. Flow cytometry was utilized to detect the ratio changes of MDSCs, G-MDSCs and M-MDSCs as well as the expression of CD86 and CD40 in macrophage, hematoxylin-eosin staining of lung and liver was utilized to detect the pathological injury, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling(TUNEL)was used to detect the apoptosis of pneumonocyte and hepatocyte and mortality analysis was reflected the severity of the disease. Based on the above indicators, we analyzed the effects of LA1 on the aggregation of MDSCs and the condition of mice in endotoxic shock. Results The ratio of MDSCs was increased by LA1 treatment for 12 and 48 hours. Further analysis of the proportions of G-MDSCs showed that LA1 treatment for 12 hours increased the proportions of G-MDSCs compared with the control group. In vitro, mRNA levels of IL-10, NOX1 and iNOS were increased after LA1 treatment in MDSCs. In vivo experiments, compared with the PBS combined LPS group, the proportions of MDSCs and G-MDSCs in LA1 combined LPS group were increased, the injuries of liver and lung were alleviated, the mortalities were reduced, and the activations of macrophage were decreased. Conclusion The activation of CD11b by LA1 alleviates endotoxin shock by promoting the aggregation of MDSCs and the expression of immunosuppressive related factors.


Assuntos
Benzoatos/farmacologia , Antígeno CD11b/agonistas , Células Supressoras Mieloides/citologia , Choque Séptico/tratamento farmacológico , Tioidantoínas/farmacologia , Animais , Feminino , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 1/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Distribuição Aleatória , Baço/citologia
7.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 34(8): 695-701, 2018 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-30384867

RESUMO

Objective To investigate the role of interleukin-16 (IL-16) in the development of inflammatory bowel disease (IBD) and clarify its regulatory mechanism involved in the pathogenesis of IBD. Methods Seven-week-old wild-type C57BL/6 (WT) and IL-16 knockout (IL-16-/-) female mice were divided into WT control group, WT dextran sulfate sodium (DSS) treatment group, IL-16-/- control group and IL-16-/- DSS treatment group. The DSS model groups were given the water with 25 g/L DSS for 7 days to establish the IBD models, while the control groups were given the normal water. During the modeling period, the body mass of mice was recorded to calculate the body mass curve. After 7 days, the whole colon of the mice was dissected and the level of IL-16 mRNA in the colon tissue was detected by real-time PCR. The level of IL-16 protein in the colon tissue was detected by ELISA. The expression and localization of IL-16 in the colon tissue were observed by immunofluorescence technique. HE staining was used to detect colonic pathological injury in mice. TUNEL assay was used to detect cell apoptosis of the colon tissue. Flow cytometry was used to detect the number and polarization of macrophages in peritoneal cells (F4/80, CD86). Immunohistochemical staining was used to detect the distribution of macrophages in the colon tissues. Real-time PCR was used to detect IL-6 and IL-12 mRNA levels in the colon tissue, and IL-6 and IL-12 protein levels were detected by ELISA. Results DSS induced high expression of IL-16 in the colon tissue. Compared with WT DSS treatment group, IL-16-/- DSS treatment group showed less changes in body mass, less colon tissue damage, and markedly lower percents of apoptotic cells in the peritoneal or colonic tissues of IL-16-/- mice. What's more, the number of macrophages, the polarization level of M1 macrophages, and the levels of the iconic inflammatory factors IL-6 and IL-12 significantly decreased in IL-16-/- DSS treatment group compared with WT DSS treatment group. Conclusion IL-16 can aggravate DSS-induced IBD by promoting the polarization of M1 macrophages.

8.
Inflammation ; 41(6): 2090-2100, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30143931

RESUMO

Endotoxin shock is a life-threatening response caused by a disordered immune response to an infection. MDSCs are accumulated and play a protective role in the pathogenesis of endotoxin shock. However, the regulation of MDSCs by small molecule remains unrevealed. Here, we report that arctigenin, a small molecule extracted from Arctium lappa, induces accumulation of functional MDSCs. Arctigenin was able to ameliorate LPS-induced inflammation through accumulating MDSCs, especially granulocytic MDSCs (G-MDSCs), and enhancing the immunosuppressive function of MDSCs in vivo and in vitro. Mechanistically, arctigenin promoted the accumulation of MDSCs through upregulating miR-127-5p which targets the 3'UTR of interferon regulatory factor-8 (IRF8) mRNA. In addition, arctigenin enhanced the immunosuppressive activity of MDSCs on M1 macrophage polarization by elevating the expression of arginase 1 (Arg-1) and inducible nitric oxide synthase (iNOS). Our study provides new insights into the regulation of functional MDSCs by arctigenin in exerting immune responses and pathogenesis of inflammatory diseases.

9.
Am J Transl Res ; 10(5): 1552-1561, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29887968

RESUMO

Cancer stem cells (CSCs) play important roles in tumor initiation, metastasis, and progression. They are also mainly responsible for high treatment failure rates. Identification and characterization of CSCs are crucial for facilitating the detection, prevention, or therapy of cancer. Great efforts have been paid to develop an effective method and the ideal method for CSCs research is still in the going. In our study, we created an ultra-low concentration of serum and non-adhesive (ULCSN) culture system to enrich CSCs from murine lewis lung cancer cell line LL/2 with cell spheres structure and characterize the LL/2 CSCs properties. Their characteristics were investigated through colony formation, spheres formation, chemoresistance, flow cytometry for putative stem cell markers, such as CD133, CD34 and CD45, immunofluorescence staining and tumor initiation capacity in vivo. Tumor spheres were formed within 7-10 days under the condition of ULCSN culture system. Compared with adherent parental LL/2 cells, the colony capacity, chemo-resistance, and expression of stem cell markers increased significantly in addition to tumor-initiating capability in the tumor sphere cells. Using the ULCSN culture system, an available isolation method of lewis lung CSCs was established, which is simple, effective, and inexpensive compared with the cytokines attachment serum free culture method. The stem cell properties of the tumor sphere LL/2 cells reflected the CSCs phenotypes. We developed a useful CSCs model for basic and pre-clinical studies for lung cancer and other types of cancer.

10.
PLoS Pathog ; 14(2): e1006884, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29447249

RESUMO

Host restriction factors constitute a formidable barrier for viral replication to which many viruses have evolved counter-measures. Human SAMD9, a tumor suppressor and a restriction factor for poxviruses in cell lines, is antagonized by two classes of poxvirus proteins, represented by vaccinia virus (VACV) K1 and C7. A paralog of SAMD9, SAMD9L, is also encoded by some mammals, while only one of two paralogs is retained by others. Here, we show that SAMD9L functions similarly to SAMD9 as a restriction factor and that the two paralogs form a critical host barrier that poxviruses must overcome to establish infection. In mice, which naturally lack SAMD9, overcoming SAMD9L restriction with viral inhibitors is essential for poxvirus replication and pathogenesis. While a VACV deleted of both K1 and C7 (vK1L-C7L-) was restricted by mouse cells and highly attenuated in mice, its replication and virulence were completely restored in SAMD9L-/- mice. In humans, both SAMD9 and SAMD9L are poxvirus restriction factors, although the latter requires interferon induction in many cell types. While knockout of SAMD9 with Crispr-Cas9 was sufficient for abolishing the restriction for vK1L-C7L- in many human cells, knockout of both paralogs was required for abolishing the restriction in interferon-treated cells. Both paralogs are antagonized by VACV K1, C7 and C7 homologs from diverse mammalian poxviruses, but mouse SAMD9L is resistant to the C7 homolog encoded by a group of poxviruses with a narrow host range in ruminants, indicating that host species-specific difference in SAMD9/SAMD9L genes serves as a barrier for cross-species poxvirus transmission.


Assuntos
Especificidade de Hospedeiro/genética , Infecções por Poxviridae/genética , Poxviridae/genética , Poxviridae/patogenicidade , Proteínas/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Células Cultivadas , Cercopithecus aethiops , Células HEK293 , Células HeLa , Humanos , Mamíferos , Camundongos , Camundongos Knockout , Células NIH 3T3 , Infecções por Poxviridae/transmissão , Infecções por Poxviridae/virologia , Proteínas/genética , Homologia de Sequência , Proteínas Supressoras de Tumor/genética , Vírus Vaccinia/genética , Vírus Vaccinia/patogenicidade , Células Vero
11.
Biochim Biophys Acta Mol Basis Dis ; 1863(11): 2796-2807, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28802852

RESUMO

Autophagy extensively participates in immune responses and inflammatory diseases. Myeloid-derived suppressor cells (MDSCs) are derived from CD11b+Gr1+ cells under pathological conditions and play an immunosuppressive role in the pathogenesis of cancer and inflammatory diseases. However, the role of autophagy in regulating the accumulation and activity of MDSCs remains unknown. In the present study, we evaluated the effects and mechanisms of autophagy on regulating accumulation and activity of MDSCs. We first found that granulocytic MDSCs (G-MDSCs), but not monocytic MDSCs (M-MDSCs), were accumulated in mice challenged by lipopolysaccharide (LPS) and showed an elevated autophagy activity. Pharmacological inhibition of autophagy significantly enhanced accumulation of G-MDSCs in vivo and in vitro. Notably, inhibition of autophagy enhanced the immunosuppressive activity of G-MDSCs on M1 macrophage polarization by promoting reactive oxygen species (ROS) production. Inhibition of autophagy promotes the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in G-MDSCs, which is required for the accumulation and activity of MDSCs. In addition, in vivo pharmacological inhibition of autophagy significantly attenuated the condition of mice challenged by LPS. Thus, we conclude that inhibition of autophagy contributes to accumulation and immunosuppressive function of G-MDSCs by promoting the activation of STAT3 signaling, suggesting that autophagy may play a critical role in regulating accumulation and activity of MDSCs. Our study provides new insights into understanding the mechanisms of autophagy in regulating immune responses and pathogenesis of inflammatory diseases.


Assuntos
Autofagia/imunologia , Granulócitos/imunologia , Células Supressoras Mieloides/imunologia , Fator de Transcrição STAT3/imunologia , Choque Séptico/imunologia , Transdução de Sinais/imunologia , Animais , Autofagia/efeitos dos fármacos , Granulócitos/patologia , Lipopolissacarídeos/toxicidade , Camundongos , Células Supressoras Mieloides/patologia , Choque Séptico/induzido quimicamente , Choque Séptico/patologia , Transdução de Sinais/efeitos dos fármacos
12.
Immunol Invest ; 46(3): 263-273, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27967259

RESUMO

Plasmacytoid dendritic cells (pDCs) exert dual roles in immune responses through inducing inflammation and maintaining immune tolerance. A switch of pDC phenotype from pro-inflammation to tolerance has therapeutic promise in the treatment of autoimmune diseases. Vinpocetine, a vasoactive vinca alkaloid extracted from the periwinkle plant, has recently emerged as an immunomodulatory agent. In this study, we evaluated the effect of vinpocetine on phenotype of pDCs isolated from C57BL/6 mice and explored its possible mechanism. Our data showed that vinpocetine significantly downregulated the expression of CD40, CD80, and CD86 on pDCs and increased the expression of translocator protein (TSPO), the specific receptor of vinpocetine, in pDCs. Vinpocetine significantly inhibited the Toll-like receptor 9 signaling pathway and reduced the secretion of related cytokines in pDCs through TSPO. Furthermore, viability of pDCs was significantly promoted by vinpocetine. These findings imply that vinpocetine serves as an immunomodulatory agent for pDCs and may be applied for the treatment of pDCs-related autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Células Dendríticas/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Alcaloides de Vinca/farmacologia , Vinca/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Ilhas de CpG/genética , Citocinas/metabolismo , Células Dendríticas/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/imunologia , Receptores de GABA/genética , Receptores de GABA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor Toll-Like 9/metabolismo
13.
Oncotarget ; 7(46): 74834-74845, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27556858

RESUMO

Dendritic cells (DCs) play a pivotal role in the development of effective immune defense while avoiding detrimental inflammation and autoimmunity by regulating the balance of adaptive immunity and immune tolerance. However, the mechanisms that govern the effector and regulatory functions of DCs are incompletely understood. Here, we show that DC-derived nitric oxide (NO) controls the balance of effector and regulatory DC differentiation. Mice deficient in the NO-producing enzyme inducible nitric oxide synthase (iNOS) harbored increased effector DCs that produced interleukin-12, tumor necrosis factor (TNF) and IL-6 but normal numbers of regulatory DCs that expressed IL-10 and programmed cell death-1 (PD-1). Furthermore, an iNOS-specific inhibitor selectively enhanced effector DC differentiation, mimicking the effect of iNOS deficiency in mice. Conversely, an NO donor significantly suppressed effector DC development. Furthermore, iNOS-/- DCs supported enhanced T cell activation and proliferation. Finally iNOS-/- mice infected with the enteric pathogen Citrobacter rodentium suffered more severe intestinal inflammation with concomitant expansion of effector DCs in colon and spleen. Collectively, our results demonstrate that DC-derived iNOS restrains effector DC development, and offer the basis of therapeutic targeting of iNOS in DCs to treat autoimmune and inflammatory diseases.


Assuntos
Diferenciação Celular , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Óxido Nítrico/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Feminino , Técnicas de Inativação de Genes , Imunidade Inata/genética , Inflamassomos/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
14.
Naunyn Schmiedebergs Arch Pharmacol ; 389(1): 33-43, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26363552

RESUMO

Liver injuries induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) are dependent on cytochrome P450 2E1 (CYP2E1). CYP2A5 can be induced by TAA but not by CCL4. In this study, liver injury including fibrosis induced by CCL4 or TAA were investigated in wild-type (WT) mice and CYP2A5 knockout (cyp2a5 (-/-) ) mice as well as in CYP2E1 knockout (cyp2e1 (-/-) ) mice as a comparison. Acute and subchronic liver injuries including fibrosis were induced by CCL4 and TAA in WT mice but not in cyp2e1 (-/-) mice, confirming the indispensable role of CYP2E1 in CCL4 and TAA hepatotoxicity. WT mice and cyp2a5 (-/-) mice developed comparable acute liver injury induced by a single injection of CCL4 as well as subchronic liver injury including fibrosis induced by 1 month of repeated administration of CCL4, suggesting that CYP2A5 does not affect CCL4-induced liver injury and fibrosis. However, while 200 mg/kg TAA-induced acute liver injury was comparable in WT mice and cyp2a5 (-/-) mice, 75 and 100 mg/kg TAA-induced liver injury were more severe in cyp2a5 (-/-) mice than those found in WT mice. After multiple injections with 200 mg/kg TAA for 1 month, while subchronic liver injury as indicated by serum aminotransferases was comparable in WT mice and cyp2a5 (-/-) mice, liver fibrosis was more severe in cyp2a5 (-/-) mice than that found in WT mice. These results suggest that while both CCL4- and TAA-induced liver injuries and fibrosis are CYP2E1 dependent, under some conditions, CYP2A5 may protect against TAA-induced liver injury and fibrosis, but it does not affect CCL4 hepatotoxicity.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cirrose Hepática/metabolismo , Tioacetamida , Alanina Transaminase/sangue , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP2E1/metabolismo , Família 2 do Citocromo P450 , Modelos Animais de Doenças , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
15.
Sci Rep ; 5: 13931, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26355080

RESUMO

Corticosteroids have been proved to be ineffective for Guillain-Barré syndrome, but the mechanism remains unknown. In a rabbit model of axonal Guillain-Barré syndrome, treatment with corticosteroids significantly reduced macrophage infiltration in the spinal ventral roots and the survival rate as well as clinical improvement. On 30(th) day after onset, there was significantly higher frequency of axonal degeneration in the corticosteroids-treated rabbits than saline-treated rabbits. Corticosteroids may reduce the scavengers that play a crucial role for nerve regeneration, thus delay the recovery of this disease.


Assuntos
Corticosteroides/farmacologia , Síndrome de Guillain-Barré/etiologia , Corticosteroides/administração & dosagem , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Modelos Animais de Doenças , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Regeneração Nervosa/efeitos dos fármacos , Coelhos
16.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 31(9): 1220-3, 2015 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-26359104

RESUMO

OBJECTIVE: To detect the expression of interleukin 16 (IL-16) in skin allografts of recipient mice and the serum level of IL-16. METHODS: Two different mouse models of skin allografts were used: the isotransplant group (C57BL/6--C57BL/6, n=45) and the allotransplantation group (BALB/c--C57BL/6, n=45). The level of IL-16 in sera and skin graft homogenates was tested by ELISA at 1, 3, 5 and 7 days after transplantation and the expression of IL-16 mRNA in skin allografts was measured by reverse transcription PCR at the same time points. RESULTS: At 3, 5 and 7 days after skin transplantation, the levels of IL-16 protein and mRNA in the skin allografts and serum level of IL-16 in the allotransplantation group were significantly higher than those in the isotransplant group. CONCLUSION: The expression of IL-16 is increased in the mouse skin allografts.


Assuntos
Interleucina-16/biossíntese , Transplante de Pele , Pele/imunologia , Aloenxertos , Animais , Interleucina-16/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
17.
Int J Clin Exp Med ; 8(5): 7107-15, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26221248

RESUMO

OBJECTIVE: Aqueous extract of Caesalpinia sappan (CSE) has immunosuppressive activities, but the mechanism remains unknown. This study was to investigate the effect of CSE on the balance between CD4(+) CD25(+) T cells and Th17 cells. METHODS: Allografted Balb/c recipients were intraperitoneally treated with CSE for 14 continuous days, and the graft survival was observed. The spleen cells and peripheral blood of the recipient mice were harvested for phenotyping by flow cytometry, detection of gene expression by real-time PCR and cytokine detection by ELISA. RESULTS: CSE prolonged skin allograft survival, increased the percentage and number of CD4(+) CD25(+) T cells, the expression of Foxp3 and STAT5 in spleen cells, the serum levels of IL-10 and TGF-ß1, whereas reduced the percentage and number of Th17 cells and serum IL-17 level in Balb/c recipients. CONCLUSION: CSE expanded CD4(+) CD25(+) T cells and decreased Th17 cells in vivo thereby improving skin allograft survival in mice, indicating that CSE affects the balance between CD4(+) CD25(+) T cells and Th17 cells in the graft to induce rejection.

18.
Mol Cell Biochem ; 406(1-2): 293-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25981534

RESUMO

The metalloprotease lethal factor (LF) from Bacillus anthracis plays a vital role in anthrax toxin action, and thus becomes a target for anti-anthrax therapy. Following the guidelines based on existing metalloprotease inhibitors, we designed a 'first-generation' LF inhibitor R9LF-1. This inhibitor was shown to be very stable by itself in a wide range of pH and temperature and able to inhibit LF activity in vitro. However, as we reported previously in the presence of LF, this inhibitor was degraded to a small molecular weight species, resulting in a significantly decreased ability to protect MAPKK from cleavage by LF as well as to protect murine macrophages from lethal toxin. In order to elucidate this unusual phenomenon to build solid basis for high-efficiency LF inhibitor development, we performed extensive research to study the effect of LF on its peptide-based inhibitor. Effects of temperature and incubation period of time on generation of the smaller peptide (short version R9LF-1) by LF as well as its catalytic domain were analyzed. We found that LF degraded R9LF-1 with maximum efficiency in the pH range of 7.0-8.5, which correlates well with the range of LF enzymatic activity with its native substrate. The degradation showed a deviation from normal hyperbolic kinetics but a similarity to the kinetics profile of an enzyme-catalyzed reaction with positive cooperativity. The short version R9LF-1 had decreased inhibitory activity toward LF; surprisingly, BIAcore results suggested a better affinity for its binding to LF. In addition, R9LF-1 was not hydrolyzed by other common proteases, such as chymotrypsin and pepsin, suggesting hydrolysis of the bond between amino acid and hydroxamate groups is unique to LF. This study calls for caution when designing peptide-based LF inhibitors and when interpreting effects of these types of inhibitors.


Assuntos
Antígenos de Bactérias/química , Toxinas Bacterianas/química , Metaloproteases/química , Oligopeptídeos/química , Inibidores de Proteases/química , Quimotripsina/química , Cinética , Ligação Proteica , Proteólise
19.
Nat Commun ; 6: 6676, 2015 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-25813085

RESUMO

Here we show that iNOS-deficient mice display enhanced classically activated M1 macrophage polarization without major effects on alternatively activated M2 macrophages. eNOS and nNOS mutant mice show comparable M1 macrophage polarization compared with wild-type control mice. Addition of N6-(1-iminoethyl)-L-lysine dihydrochloride, an iNOS inhibitor, significantly enhances M1 macrophage polarization while S-nitroso-N-acetylpenicillamine, a NO donor, suppresses M1 macrophage polarization. NO derived from iNOS mediates nitration of tyrosine residues in IRF5 protein, leading to the suppression of IRF5-targeted M1 macrophage signature gene activation. Computational analyses corroborate a circuit that fine-tunes the expression of IL-12 by iNOS in macrophages, potentially enabling versatile responses based on changing microenvironments. Finally, studies of an experimental model of endotoxin shock show that iNOS deficiency results in more severe inflammation with an enhanced M1 macrophage activation phenotype. These results suggest that NO derived from iNOS in activated macrophages suppresses M1 macrophage polarization.


Assuntos
Polaridade Celular/genética , Macrófagos/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Choque Séptico/imunologia , Animais , Polaridade Celular/efeitos dos fármacos , Modelos Animais de Doenças , Fatores Reguladores de Interferon/metabolismo , Lisina/análogos & derivados , Lisina/farmacologia , Ativação de Macrófagos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/citologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , S-Nitroso-N-Acetilpenicilamina/farmacologia
20.
J Med Virol ; 86(10): 1780-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24699993

RESUMO

The signal peptide Ag85B of Bacillus Chalmette-Guerin (BCG) was used to construct a recombinant plasmid of BCG. The BCG-Ag85B gene and fused EBV LMP2A and BZLF1 genes were amplified and successively inserted into the Escherichia coli-BCG shuttle-vector pMV261. The recombinant plasmids were then amplified in E. coli DH5α and transformed into competent BCG. The expression of BZLF1 and LMP2A fusion proteins in recombinant-BCG (rBCG) was shown by Western blot. After the injection of recombinant-BCG into mice, antibodies against the fusion protein BZLF1 and LMP2A were measured by ELISA, and the cellular immune effects were determined by the lactate dehydrogenate (LDH) release assays. The results confirmed that the cloned genes of BCG-Ag85B and Z2A were correctly inserted into the vector pMV261. The recombinant plasmid pMVZ2A expressed Z2A in BCG effectively after transformation. The rBCG proteins were recognized by the BZLF1 (LMP2A) antibody. An ELISA demonstrated that rBCG could stimulate the generation of antibody against the fusion protein. The fusion gene was constructed successfully, and the rBCG induced humoral and cellular immune response in mice.


Assuntos
Vetores Genéticos , Mycobacterium bovis/genética , Transativadores/imunologia , Proteínas da Matriz Viral/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Transativadores/genética , Vacinação/métodos , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Proteínas da Matriz Viral/genética , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
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