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1.
Rev. ADM ; 80(3): 133-138, mayo-jun. 2023. ilus, tab
Artigo em Espanhol | LILACS | ID: biblio-1517474

RESUMO

Introducción: las metaloproteinasas son enzimas que participan en la remodelación tisular y su función se relaciona con procesos fisiológicos y patológicos, como la invasión y la metástasis. El ameloblastoma convencional (AMC) es una neoplasia epitelial benigna odontogénica intraósea caracterizada por una progresión lenta y localmente invasiva, cuyo crecimiento se ha vinculado con el recambio ósea y la remodelación de la matriz extracelular. El objetivo del presente trabajo fue determinar la presencia inmunohistoquímica de MMP-1, MMP-2 y MMP-9 en el AMC. Material y métodos: se realizó un estudio piloto observacional analítico utilizando cinco muestras de AMC. Los especímenes fueron recolectados aleatoriamente del archivo del Departamento de Patología Oral y Maxilofacial, de la Escuela Nacional de Estudios Superiores (ENES) Unidad León, UNAM. Como grupo control se emplearon dos especímenes de folículo dental, obtenido de pacientes con indicación de su extracción por motivos ortodóncicos. Se realizó la técnica de inmunohistoquímica por peroxidasa, recolectando el nivel y proporción de inmunoexpresión de manera semicuantitativa. Resultados: cuatro pacientes fueron de género masculino y uno femenino, la edad promedio fue de 40.6 ± 14.9 años. Todas las muestras fueron obtenidas de la región mandibular posterior. Se observaron dos especímenes con patrón folicular y tres con plexiforme. Las MMP-2 y MMP-9 se detectaron sólo en uno de los cinco especímenes y únicamente en el parénquima de la lesión, con una proporción de 100%. Conclusión: según nuestro análisis inmunohistoquímico, las MMP-2 y MMP-9 son las metaloproteinasas que presentaron expresión positiva dentro de la patogénesis del AMC comparado a la MMP-1; no obstante, es necesario realizar este tipo de estudios en una población mayor (AU)


Introduction: metalloproteinases are enzymes involved in tissue remodeling and their function is related to physiological and pathological processes, such as invasion and metastasis. These enzymes are capable of degrading components of the extracellular matrix, which may promote tumor progression. Conventional ameloblastoma (CA) is described as a benign intraosseous epithelial odontogenic neoplasm characterized by a slow and locally invasive progression, whose growth has been linked to bone turnover and extracellular matrix remodeling. The aim of the present work was to determine the immunohistochemical presence of MMP-1, MMP-2 and MMP-9 in CA. Material and methods: an analytical observational pilot study was performed using 5 CA, randomly collected from the archive of the Department of Oral and Maxillofacial Pathology, Escuela Nacional de Estudios Superiores (ENES) Unidad León, UNAM. The control group used were two dental follicle samples, obtained from patients with extraction indication for orthodontic treatment. The peroxidase immunohistochemistry assay was performed, collecting semiquantitatively level and proportion of immunoexpression. Results: four patients were male and one female, the average age was 40.6 ± 14.9 years. All specimens were obtained from the posterior mandibular region. Two specimens were observed with follicular pattern and three with plexiform pattern. MMP-2 and MMP-9 were detected only in one of the five specimens, with presence in the parenchyma of the lesion, with a proportion of 100% of the cell analyzed. Conclusion: according to our immunohistochemical analysis, MMP-2 and MMP-9 are the metalloproteinases that presented positive expression within the pathogenesis of CA compared to MMP-1; however, it is necessary to perform this type of studies in a larger population (AU)


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Imuno-Histoquímica/métodos , Metaloproteinase 2 da Matriz/imunologia , Metaloproteinase 9 da Matriz/imunologia , Metaloproteinase 1 da Matriz/imunologia , México
2.
Front Immunol ; 12: 593595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995342

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1ß, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.


Assuntos
COVID-19 , Citocinas , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Metaloproteinase 1 da Matriz , Metaloproteinase 3 da Matriz , Receptores Imunológicos , Adulto , Idoso , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/metabolismo , Influenza Humana/sangue , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Masculino , Metaloproteinase 1 da Matriz/sangue , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 3 da Matriz/sangue , Metaloproteinase 3 da Matriz/imunologia , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores Imunológicos/sangue , Receptores Imunológicos/imunologia , Células Th1/imunologia , Células Th2/imunologia
3.
BMC Complement Med Ther ; 21(1): 43, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485352

RESUMO

BACKGROUND: Periodontitis is a chronic infection initiated by oral bacterial and their virulence factors, yet the severity of periodontitis is largely determined by the dysregulated host immuno-inflammatory response. Baicalein is a flavonoid extracted from Scutellaria baicalensis with promising anti-inflammatory properties. This study aims to clarify the anti-inflammatory and osteogenic effects of baicalein in periodontal ligament cells (PDLCs) treated with lipopolysaccharides (LPS). METHODS: Human PDLCs were incubated with baicalein (0-100 µM) for 2 h prior to LPS challenge for 24 h. MTT analysis was adopted to assess the cytoxicity of baicalein. The mRNA and protein expression of inflammatory and osteogenic markers were measured by real-time polymerase chain reaction (PCR), western blot and enzyme-linked immunosorbent assay (ELISA) as appropriate. Alkaline phosphatase (ALP) and Alizarin red S (ARS) staining were performed to evaluate the osteogenic differentiation of PDLCs. The expression of Wnt/ß-catenin and mitogen-activated protein kinase (MAPK) signaling related proteins was assessed by western blot. RESULTS: MTT results showed that baicalein up to 100 µM had no cytotoxicity on PDLCs. Baicalein significantly attenuated the inflammatory factors induced by LPS, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), matrix metalloprotein-1 (MMP-1), MMP-2 and monocyte chemoattractant protein 1 (MCP-1) at both mRNA and protein level. Moreover, MAPK signaling (ERK, JNK and p38) was significantly inhibited by baicalein, which may account for the mitigated inflammatory response. Next, we found that baicalein effectively restored the osteogenic differentiation of LPS-treated PDLCs, as shown by the increased ALP and ARS staining. Accordingly, the protein and gene expression of osteogenic markers, namely runt-related transcription factor 2 (RUNX2), collagen-I, and osterix were markedly upregulated. Importantly, baicalein could function as the Wnt/ß-catenin signaling activator, which may lead to the increased osteoblastic differentiation of PDLCs. CONCLUSIONS: With the limitation of the study, we provide in vitro evidence that baicalein ameliorates inflammatory response and restores osteogenesis in PDLCs challenged with LPS, indicating its potential use as the host response modulator for the management of periodontitis.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Osteogênese/efeitos dos fármacos , Ligamento Periodontal/efeitos dos fármacos , Periodontite/tratamento farmacológico , Scutellaria baicalensis/química , Fosfatase Alcalina/genética , Fosfatase Alcalina/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/efeitos adversos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Ligamento Periodontal/citologia , Ligamento Periodontal/imunologia , Periodontite/genética , Periodontite/imunologia , Periodontite/fisiopatologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética , beta Catenina/imunologia
4.
Clin Immunol ; 220: 108579, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32866644

RESUMO

Endoplasmic reticulum (ER) stress associated proteins contribute to the pathogenesis of rheumatoid arthritis (RA) through affecting synoviocyte proliferation and proinflammatory cytokine production. The role of DERL3, an ER-associated degradation component, in joint inflammation of RA was explored. Synovial tissues from RA and osteoarthritis (OA) patients were collected, and in RA synovial tissue, DERL3 showed up-regulation and significantly positive correlation with the expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-1. Immunofluorescence result suggested DERL3 was located in fibroblast-like synoviocytes (FLS). Among different inflammatory stimuli, DERL3 could be up-regulated by TNF-α stimulation in FLS. Under TNF-α stimulation, knocking down DERL3, the expression of IL-6, IL-8, MMP-1, MMP-13 was reduced and the activation of nuclear factor kappa B (NF-κB) signaling pathway was inhibited. In pristane-induced arthritis (PIA) rat model, Derl3 was up-regulated in synovial tissue and disease was attenuated after intraarticular injection of siDerl3. Overall, we conclude that TNF-α inducing DERL3 expression promotes the inflammation of FLS through activation of NF-κB signaling pathway, suggesting DERL3 plays important roles in the pathogenesis of RA and is a promising therapeutic target.


Assuntos
Artrite Reumatoide/imunologia , Proteínas de Membrana/imunologia , Sinoviócitos/imunologia , Idoso , Animais , Artrite Experimental/imunologia , Células Cultivadas , Citocinas/imunologia , Feminino , Humanos , Masculino , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 13 da Matriz/imunologia , Camundongos , Pessoa de Meia-Idade , NF-kappa B/imunologia , Osteoartrite/imunologia , Ratos , Transdução de Sinais
5.
Am J Chin Med ; 47(8): 1853-1868, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31786945

RESUMO

Skin is the outer tissue layer and is a barrier protecting the body from various external stresses. The fresh water green edible algae Prasiola japonica has antiviral, antimicrobial, and anti-inflammatory properties; however, few studies of its effects on skin-protection have been reported. In this study, Prasiola japonica ethanol extract (Pj-EE) was prepared, and its skin-protective properties were investigated in skin keratinocytes. Pj-EE inhibited ROS production in UVB-irradiated HaCaT cells without cytotoxicity. Pj-EE also suppressed the apoptotic death of UVB-irradiated HaCaT cells by decreasing the generation of apoptotic bodies and the proteolytic activation of apoptosis caspase-3, -8, and -9. Moreover, Pj-EE downregulated the mRNA expression of the inflammatory gene cyclooxygenase-2 (COX-2), the pro-inflammatory cytokine genes interleukin (IL)-1ß, IL-8, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, and the tissue remodeling genes matrix metalloproteinase (MMP)-1, -2, -3, and -9. The Pj-EE-induced anti-inflammatory effect was mediated by suppressing the activation of nuclear factor-kappa B (NF-κB) signaling pathway in the UVB-irradiated HaCaT cells. Taken together, these results suggest that Pj-EE exerts skin-protective effects through anti-oxidant, anti-apoptotic, and anti-inflammatory activities in skin keratinocytes.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Clorófitas/química , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Extratos Vegetais/farmacologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Humanos , Interferon gama/genética , Interferon gama/imunologia , Queratinócitos/citologia , Queratinócitos/imunologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Substâncias Protetoras/farmacologia , Pele/citologia , Pele/imunologia , Raios Ultravioleta
6.
J Immunol Res ; 2019: 6929286, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828173

RESUMO

OBJECTIVE: Iguratimod, a novel disease-modifying anti-rheumatic drug for the treatment of rheumatoid arthritis, has been approved in China and Japan. Here, we aimed to find whether iguratimod can inhibit the aggressive behavior and promote apoptosis of rheumatoid fibroblast-like synoviocytes (RA-FLSs). METHODS: The proliferation of RA-FLSs was assessed by 5-ethynyl-2'-deoxyuridine test and Cell Counting Kit-8. Migration and invasion were determined by the wound test and a transwell assay. Apoptosis was tested by flow cytometry. The mRNA expression of matrix metalloproteinases (MMPs) and proinflammatory cytokines in RA-FLSs were measured by quantitative PCR and ELISA. To gain insight into the molecular signaling mechanisms, we determined the effect of iguratimod on the activation of mitogen-activated protein kinases (MAPK) signaling pathways by the cellular thermal shift assay (CETSA) and western blot. RESULTS: Iguratimod treatment significantly reduced the proliferation, migration, and invasive capacities of RA-FLSs in a dose-dependent manner in vitro. MMP-1, MMP-3, MMP-9, Interleukin-6 (IL-6), and monocyte chemoattractant protein-1 mRNA and protein levels were all decreased after treatment with iguratimod. Furthermore, tumor necrosis factor-alpha- (TNF-α-) induced expression of phosphorylated c-Jun N-terminal kinases (JNK) and P38 MAPK were inhibited by iguratimod. Additionally, iguratimod promoted the apoptosis of RA-FLSs. Most importantly, iguratimod was shown to directly interact with JNK and P38 protein by CETSA assay. Moreover, activating transcription factor 2 (ATF-2), a substrate of both JNK and P38, was suppressed by iguratimod. CONCLUSIONS: Our findings suggested that the therapeutic effects of iguratimod on RA might be, in part, due to targeting the aggressive behavior and apoptosis of RA-FLSs.


Assuntos
Antirreumáticos/farmacologia , Cromonas/farmacologia , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Imunossupressores/farmacologia , Sulfonamidas/farmacologia , Sinoviócitos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/cirurgia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/imunologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Cultura Primária de Células , Transdução de Sinais , Sinovectomia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinoviócitos/imunologia , Sinoviócitos/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
7.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31383744

RESUMO

Reproductive tract pathology caused by Chlamydia trachomatis infection is an important global cause of human infertility. To better understand the mechanisms associated with Chlamydia-induced genital tract pathogenesis in humans, we used CRISPR genome editing to disrupt Toll-like receptor 3 (TLR3) function in the human oviduct epithelial (hOE) cell line OE-E6/E7 in order to investigate the possible role(s) of TLR3 signaling in the immune response to Chlamydia Disruption of TLR3 function in these cells significantly diminished the Chlamydia-induced synthesis of several inflammation biomarkers, including interferon beta (IFN-ß), interleukin-6 (IL-6), interleukin-6 receptor alpha (IL-6Rα), soluble interleukin-6 receptor beta (sIL-6Rß, or gp130), IL-8, IL-20, IL-26, IL-34, soluble tumor necrosis factor receptor 1 (sTNF-R1), tumor necrosis factor ligand superfamily member 13B (TNFSF13B), matrix metalloproteinase 1 (MMP-1), MMP-2, and MMP-3. In contrast, the Chlamydia-induced synthesis of CCL5, IL-29 (IFN-λ1), and IL-28A (IFN-λ2) was significantly increased in TLR3-deficient hOE cells compared to their wild-type counterparts. Our results indicate a role for TLR3 signaling in limiting the genital tract fibrosis, scarring, and chronic inflammation often associated with human chlamydial disease. Interestingly, we saw that Chlamydia infection induced the production of biomarkers associated with persistence, tumor metastasis, and autoimmunity, such as soluble CD163 (sCD163), chitinase-3-like protein 1, osteopontin, and pentraxin-3, in hOE cells; however, their expression levels were significantly dysregulated in TLR3-deficient hOE cells. Finally, we demonstrate using hOE cells that TLR3 deficiency resulted in an increased amount of chlamydial lipopolysaccharide (LPS) within Chlamydia inclusions, which is suggestive that TLR3 deficiency leads to enhanced chlamydial replication and possibly increased genital tract pathogenesis during human infection.


Assuntos
Chlamydia trachomatis/imunologia , Células Epiteliais/microbiologia , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno/imunologia , Receptor 3 Toll-Like/imunologia , Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Linhagem Celular Transformada , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Chlamydia trachomatis/crescimento & desenvolvimento , Chlamydia trachomatis/patogenicidade , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/imunologia , Células Epiteliais/imunologia , Tubas Uterinas/imunologia , Tubas Uterinas/microbiologia , Feminino , Deleção de Genes , Células HeLa , Interações Hospedeiro-Patógeno/genética , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/genética , Interleucinas/imunologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Transdução de Sinais , Receptor 3 Toll-Like/deficiência , Receptor 3 Toll-Like/genética
8.
Cell Physiol Biochem ; 51(4): 1830-1838, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504721

RESUMO

BACKGROUND/AIMS: Osteoarthritis (OA) is a multifactorial disease that is associated with inflammation in joints. The purpose of the present study was to investigate the anti-inflammatory activity and mechanism of morin on human osteoarthritis chondrocytes stimulated by IL-1ß. METHODS: The levels of NO and PGE2 were measured by the Griess method and ELISA. The levels of MMP1, MMP3, and MMP13 were also measured by ELISA. RESULTS: The results revealed that IL-1ß significantly increased the production of NO, PGE2, MMP1, MMP3, and MMP13. Additionally, the increases were significantly attenuated by treatment with morin. Furthermore, IL-1ß-induced NF-κB activation was suppressed by morin. In addition, the expression of Nrf2 and HO-1 were increased by morin and knockdown of Nrf2 could prevent the anti-inflammatory effects of morin. CONCLUSION: In conclusion, this study suggested that morin attenuated IL-1ß-induced inflammation by activating the Nrf2 signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Flavonoides/farmacologia , Interleucina-1beta/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Osteoartrite/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/imunologia , Condrócitos/patologia , Humanos , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 13 da Matriz/imunologia , Metaloproteinase 3 da Matriz/imunologia , Pessoa de Meia-Idade , Óxido Nítrico/imunologia , Osteoartrite/imunologia , Osteoartrite/patologia , Transdução de Sinais/efeitos dos fármacos
9.
J Plant Physiol ; 218: 189-195, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28888160

RESUMO

We previously isolated Nicotiana benthamiana matrix metalloprotease 1 (NMMP1) from tobacco leaves. The NMMP1 gene encodes a highly conserved, Zn-containing catalytic protease domain that functions as a factor in the plant's defense against bacterial pathogens. Expression of NMMP1 was strongly induced during interactions between tobacco and one of its pathogens, Phytophthora infestans. To elucidate the role of the NMMP1 in defense of N. benthamiana against fungal pathogens, we performed gain-of-function and loss-of-function studies. NMMP1-overexpressing plants had stronger resistance responses against P. infestans infections than control plants, while silencing of NMMP1 resulted in greater susceptibility of the plants to the pathogen. This greater susceptibility correlated with fewer NMMP1 transcripts than the non-silenced control. We also examined cell death as a measure of disease. The amount of cell death induced by the necrosis-inducing P. infestans protein 1, PiNPP1, was dependent on NMMP1 in N. benthamiana. Potato plants overexpressing NMMP1 also had enhanced disease resistance against P. infestans. RT-PCR analysis of these transgenic potato plants revealed constitutive up-regulation of the potato defense gene NbPR5. NMMP1-overexpressing potato plants were taller and produced heavier tubers than control plants. We suggest a role for NMMP1in pathogen defense and development.


Assuntos
Resistência à Doença , Metaloproteinase 1 da Matriz/genética , Nicotiana/genética , Phytophthora infestans/fisiologia , Doenças das Plantas/genética , Proteínas de Plantas/genética , Solanum tuberosum/imunologia , Metaloproteinase 1 da Matriz/imunologia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/imunologia , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/imunologia , Plantas Geneticamente Modificadas/microbiologia , Solanum tuberosum/genética , Solanum tuberosum/microbiologia , Nicotiana/imunologia , Nicotiana/microbiologia , Regulação para Cima
10.
PLoS Pathog ; 13(6): e1006367, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28570642

RESUMO

Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission.


Assuntos
Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Animais , Humanos , Macrófagos/microbiologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/genética , Complexos Multiproteicos/imunologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/fisiologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
11.
Infect Genet Evol ; 49: 212-220, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28119029

RESUMO

FLI1 (Friend leukemia virus integration 1) and IL6 (interleukin 6; IL-6) are associated with Leishmania braziliensis susceptibility. Cutaneous lesions show exaggerated matrix metalloproteinase 1 (MMP1). In other skin diseases, FLI1 promoter methylation reduces FLI1 expression, and low FLI1 down-regulates MMP1. IL-6 increases FLI1 expression. We hypothesized that epigenetic regulation of FLI1 in cutaneous leishmaniasis, together with IL-6, might determine MMP1 expression. While generally low (<10%), percent FLI1 promoter methylation was lower (P=0.001) in lesion biopsies than normal skin. Contrary to expectation, a strong positive correlation occurred between FLI1 methylation and gene expression in lesions (r=0.98, P=0.0005) and in IL-6-treated L. braziliensis-infected macrophages (r=0.99, P=0.0004). In silico analysis of the FLI1 promoter revealed co-occurring active H3K27ac and repressive DNA methylation marks to enhance gene expression. FLI1 expression was enhanced between 3 and 24hour post infection in untreated (P=0.0002) and IL-6-treated (P=0.028) macrophages. MMP1 was enhanced in lesion biopsies (P=0.0002), induced (P=0.007) in infected macrophages, but strongly inhibited by IL-6. No correlations occurred between FLI1 and MMP1 expression in lesions or infected macrophages (with/without IL-6). We conclude that MMP1 is regulated by factors other than FLI1, and that the influence of IL-6 on MMP1 was independent of its effect on FLI1.


Assuntos
Epigênese Genética , Interações Hospedeiro-Patógeno , Interleucina-6/genética , Leishmaniose Cutânea/genética , Metaloproteinase 1 da Matriz/genética , Proteína Proto-Oncogênica c-fli-1/genética , Adolescente , Adulto , Criança , Metilação de DNA , Feminino , Regulação da Expressão Gênica , Histonas/genética , Histonas/imunologia , Humanos , Interleucina-6/imunologia , Leishmania braziliensis/patogenicidade , Leishmania braziliensis/fisiologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Metaloproteinase 1 da Matriz/imunologia , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-fli-1/imunologia , Pele/imunologia , Pele/patologia
12.
J Neurovirol ; 23(3): 369-375, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27995575

RESUMO

In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/µL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid ß42. Individuals with CD4 351-500 cells/µL (N = 40) had significantly higher CSF levels of interleukin (IL)-1ß, amyloid ß42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.


Assuntos
Complexo AIDS Demência/líquido cefalorraquidiano , Complexo AIDS Demência/diagnóstico , Linfócitos T CD4-Positivos/imunologia , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/fisiopatologia , Adulto , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/imunologia , Biomarcadores/líquido cefalorraquidiano , Fator Neurotrófico Derivado do Encéfalo/líquido cefalorraquidiano , Fator Neurotrófico Derivado do Encéfalo/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/líquido cefalorraquidiano , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interleucina-12/líquido cefalorraquidiano , Interleucina-12/imunologia , Interleucina-2/líquido cefalorraquidiano , Interleucina-2/imunologia , Masculino , Metaloproteinase 1 da Matriz/líquido cefalorraquidiano , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 7 da Matriz/líquido cefalorraquidiano , Metaloproteinase 7 da Matriz/imunologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/imunologia , Fator de Crescimento Derivado de Plaquetas/líquido cefalorraquidiano , Fator de Crescimento Derivado de Plaquetas/imunologia , Estudos Prospectivos , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptor para Produtos Finais de Glicação Avançada/imunologia , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Subunidade beta da Proteína Ligante de Cálcio S100/imunologia , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/imunologia , Uganda
13.
Mol Med Rep ; 15(2): 981-987, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28035387

RESUMO

The present study aimed to investigate the therapeutic mechanisms of nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids in osteoarthritis (OA). The CHON­002 human chondrocyte cell line was used in the study. The levels of the cytokines, interleukin (IL)­1ß, IL­6, IL­8 and IL­10, released by cells treated with tumor necrosis factor­α (TNF­α) were determined by ELISA. Levels of collagen I, aggrecan, matrix metalloproteinase (MMP)­1, MMP­13, signal transducer and activator of transcription (STAT) 3, nuclear factor­κB (NF­κB) subunit p65 and inhibitory subunit of NF­κB (IκB) following treatment with IL­1ß, IL­6, IL­8 or IL­10 were assessed by western blot. Levels of IL­6 and IL­8 were measured by ELISA following administration of TNF­α combined with certain drugs. In addition, these parameters were evaluated by western blot following incubation with drugs in combination with IL­6 or IL­8 and after knockdown of STAT3, by addition of small interfering RNA (siRNA)­STAT3 (siSTAT3), an inhibitor of the proteasome (MG132) or both. IL­1ß, IL­6, IL­8 and IL-10 were upregulated by TNF­α. Addition of IL­6 or IL­8 led to increased collagen I, MMP­1 and MMP­13 protein levels, and also promoted STAT3 phosphorylation and increased the expression of NF­κB subunit p65, but had no effect on aggrecan protein levels. When siSTAT3 and MG132 treatment was combined, levels of collagen I, MMP­1 and MMP­13 were reduced. Additionally, levels of IL­6 and IL­8 were significantly decreased by prednisone, ibuprofen and betamethasone. However, no significant differences were observed following treatment with piroxicam or indomethacin. In combination with IL­6 or IL­8, prednisone, ibuprofen and betamethasone significantly reduced the levels of collagen I, MMP­1 and MMP­13, and inactivated NF­κB and STAT3 pathways. In conclusion, prednisone, ibuprofen and betamethasone may prevent OA by suppressing the expression of IL­6 and IL­8, subsequently inactivating NF­κB and STAT3 pathways, and ultimately, leading to decreased levels of collagen I, MMP­1, and MMP­13.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Betametasona/uso terapêutico , Condrócitos/efeitos dos fármacos , Ibuprofeno/uso terapêutico , Osteoartrite/tratamento farmacológico , Prednisona/uso terapêutico , Agrecanas/imunologia , Linhagem Celular , Condrócitos/imunologia , Colágeno Tipo I/imunologia , Humanos , Interleucinas/imunologia , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 13 da Matriz/imunologia , Osteoartrite/imunologia , Fator de Necrose Tumoral alfa/imunologia
14.
Molecules ; 22(1)2016 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-28036032

RESUMO

The accumulation and infiltration of mast cells are found in osteoarthritic lesions in humans and rodents. Nonetheless, the roles of mast cells in osteoarthritis are almost unknown. Although Viscum coloratum has various beneficial actions, its effect on allergic and osteoarthritic responses is unknown. In this study, we established an in vitro model of mast cell-mediated osteoarthritis and investigated the effect of the ethanol extract of Viscum coloratum (VEE) on IgE/antigen (IgE/Ag)-activated mast cells and mast cell-derived inflammatory mediator (MDIM)-stimulated chondrocytes. The anti-allergic effect of VEE was evaluated by degranulation, inflammatory mediators, and the FcεRI signaling cascade in IgE/Ag-activated RBL-2H3 cells. The anti-osteoarthritic action of VEE was evaluated by cell migration, and the expression, secretion, and activity of MMPs in MDIM-stimulated SW1353 cells. VEE significantly inhibited degranulation (IC50: 93.04 µg/mL), the production of IL-4 (IC50: 73.28 µg/mL), TNF-α (IC50: 50.59 µg/mL), PGD2 and LTC4, and activation of the FcεRI signaling cascade in IgE/Ag-activated RBL-2H3 cells. Moreover, VEE not only reduced cell migration but also inhibited the expression, secretion, and/or activity of MMP-1, MMP-3, or MMP-13 in MDIM-stimulated SW1353 cells. In conclusion, VEE possesses both anti-allergic and anti-osteoarthritic properties. Therefore, VEE could possibly be considered a new herbal drug for anti-allergic and anti-osteoarthritic therapy. Moreover, the in vitro model may be useful for the development of anti-osteoarthritic drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Condrócitos/imunologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Osteoartrite/tratamento farmacológico , Extratos Vegetais/farmacologia , Viscum/química , Animais , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imunoglobulina E/imunologia , Mediadores da Inflamação/metabolismo , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 13 da Matriz/imunologia , Metaloproteinase 3 da Matriz/imunologia , Osteoartrite/patologia , Ratos , Receptores de IgE/imunologia , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
15.
Mol Med Rep ; 14(4): 3935-40, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27574042

RESUMO

Psoriasis is a debilitating chronic inflammatory disease. In addition to the characteristic effects on the skin, chronic inflammation associated with the disease is recognized to contribute to cardiovascular, hepatic and renal comorbidities. Immature myeloid regulatory cells, known as myeloid­derived suppressor cells (MDSCs), have been demonstrated to accumulate in various diseases and chronic inflammatory states, including inflammatory bowel disease and various types of cancer. The results of the present study, obtained using flow cytometry and cell culture analysis of peripheral blood mononuclear cells from psoriasis and healthy patients, revealed that MDSC levels are significantly increased in the blood of patients with psoriasis compared with healthy controls. Furthermore, these cells are capable of producing various molecules, including matrix metalloproteinase­9 and­1, interleukin­8, growth­related oncogene, and monocyte chemoattractant protein 1. These molecules may recruit additional immune cells involved in the pathogenesis of the disease, and contribute to the chronic inflammatory state in these patients. Therefore, MDSCs, which have various immune regulatory functions, may contribute to the pathogenesis of psoriasis as a systemic inflammatory disease.


Assuntos
Inflamação/patologia , Células Supressoras Mieloides/patologia , Psoríase/patologia , Adulto , Quimiocina CCL2/análise , Quimiocina CCL2/imunologia , Feminino , Humanos , Inflamação/complicações , Inflamação/imunologia , Interleucina-8/análise , Interleucina-8/imunologia , Masculino , Metaloproteinase 1 da Matriz/análise , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/imunologia , Pessoa de Meia-Idade , Células Supressoras Mieloides/imunologia , Psoríase/complicações , Psoríase/imunologia
16.
Tsitologiia ; 58(1): 23-9, 2016.
Artigo em Russo | MEDLINE | ID: mdl-27220248

RESUMO

We have examined peripheral blood neutrophils from 123 patients with primary endometrial cancer at stage Ia. Receptor system and the ability of neutrophils to form extracellular traps were assessed by fluorescence microscopy, the spontaneous production of cytokines IL-2, IFN-γ, g-CSF, matrix metalloproteinases-1,9,13 by the method of enzyme-linked immunosorbent assay, phagocytic activity, myeloperoxidase activity, the level of cationic proteis activity in NBT-test were evaluated by cytochemical methods, activity of neutrophils in the spontaneous NBT-test was used to evaluate the oxygen-dependent bactericidal action of neutrophils. The topology and the rigidity of the membrane of neutrophils were assessed by scanning probe microscopy. We have shown that the increase in the relative number of neutrophils lead to a change in their receptor system, aerobic and anaerobic cytotoxicity and ability to phagocytosis are enchanced while reducing NET-activity. We have observed a change in the secretory activity of neutrophils, which is characterized by increased level of MMP-1, possibly initiated by enhanced production of reactive oxygen species, by a reduction in the IL-2 level (inductor of cytotoxic activity) and a sharp increase in the level of the G-CSF. Architectonics of neutrophils in the case of endonetrial cancer at stage Ia is characterized by changing the shape and loss of grit. The rigidity of the cell membrane decreased. Changes in the morphology of neutrophils on the background of the continuing hyperactivity suggests that a state of balance between the immune system and the tumor is already in stage Ia endometrial cancer.


Assuntos
Membrana Celular/ultraestrutura , Neoplasias do Endométrio/patologia , Armadilhas Extracelulares/química , Regulação Neoplásica da Expressão Gênica , Neutrófilos/ultraestrutura , Fenótipo , Membrana Celular/química , Armadilhas Extracelulares/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/imunologia , Humanos , Imunofenotipagem , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/imunologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Fluidez de Membrana , Microscopia de Força Atômica , Estadiamento de Neoplasias , Neutrófilos/metabolismo , Peroxidase/genética , Peroxidase/imunologia , Fagocitose , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
17.
Sci Rep ; 7: 20077, 2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26822278

RESUMO

To inhibit the immune inflammation in the allografts can be beneficial to organ transplantation. This study aims to induce the donor antigen specific regulatory T cells (Treg cell) inhibit the immune inflammation in the allograft heart. In this study, peripheral exosomes were purified from the mouse serum. A heart transplantation mouse model was developed. The immune inflammation of the allograft heart was assessed by histology and flow cytometry. The results showed that the donor antigen-specific T helper (Th)2 pattern inflammation was observed in the allograft hearts; the inflammation was inhibited by immunizing the recipient mice with the donor-derived exosomes. Purified peripheral exosomes contained integrin MMP1a; the latter induced CD4(+) T cells to express Fork head protein-3 and transforming growth factor (TGF)-ß via inhibiting the Th2 transcription factor, GATA binding protein 3, in CD4(+) T cells. Administration with the donor-derived exosomes significantly prolonged the allograft heart survival. We conclude that the donor-derived peripheral exosomes have the capacity to inhibit the immune inflammation in the allograft heart via inducing specific Treg cells, implicating that administration with the donor-derived exosomes may be beneficial to cardiac transplantation.


Assuntos
Exossomos/imunologia , Transplante de Coração , Tolerância Imunológica , Inflamação/imunologia , Aloenxertos/imunologia , Animais , Antígenos/imunologia , Células Dendríticas/imunologia , Exossomos/metabolismo , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Inflamação/patologia , Metaloproteinase 1 da Matriz/imunologia , Camundongos , Linfócitos T Reguladores/imunologia , Doadores de Tecidos
18.
Arthritis Rheumatol ; 68(5): 1111-23, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26713842

RESUMO

OBJECTIVE: Synovial fibroblasts (SFs) produce matrix-degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs. METHODS: MMP gene expression and histone methylation profiles in the MMP promoters were examined in RASFs. The effect of WD repeat domain 5 (WDR5) silencing on histone methylation and MMP gene expression in RASFs was analyzed. MMP gene expression, surface expression of the interleukin-6 (IL-6) receptor, phosphorylation of STAT-3, and binding of STAT-3 in the MMP promoters were investigated in RASFs stimulated with IL-6. RESULTS: The MMP-1, MMP-3, MMP-9, and MMP-13 genes were actively transcribed in RASFs. Correspondingly, the level of histone H3 trimethylated at lysine 4 (H3K4me3) was elevated, whereas that of H3K27me3 was suppressed in the MMP promoters in RASFs. The decrease in H3K4me3 via WDR5 small interfering RNA reduced the levels of messenger RNA for MMP-1, MMP-3, MMP-9, and MMP-13 in RASFs. Interestingly, IL-6 signaling significantly increased the expression of MMP-1, MMP-3, and MMP-13, but not MMP-9, in RASFs. Although the IL-6 signaling pathway was similarly active in RASFs and osteoarthritis SFs, STAT-3 bound to the MMP-1, MMP-3, and MMP-13 promoters, but not the MMP-9 promoter, after IL-6 stimulation in RASFs. CONCLUSION: Our findings indicate that histone methylation and STAT-3 regulate spontaneous and IL-6-induced MMP gene activation in RASFs. The combination of chromatin structure and transcription factors may regulate distinct arthritogenic properties of RASFs.


Assuntos
Artrite Reumatoide/genética , Fibroblastos/metabolismo , Regulação da Expressão Gênica/imunologia , Histonas/metabolismo , Interleucina-6/imunologia , Metaloproteinases da Matriz/genética , Fator de Transcrição STAT3/imunologia , Membrana Sinovial/citologia , Artrite Reumatoide/imunologia , Western Blotting , Estudos de Casos e Controles , Imunoprecipitação da Cromatina , Fibroblastos/imunologia , Citometria de Fluxo , Código das Histonas , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/imunologia , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/imunologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Metaloproteinases da Matriz/imunologia , Metilação , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/imunologia , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ativação Transcricional
19.
PLoS One ; 10(9): e0137979, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26367274

RESUMO

BACKGROUND: Tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) are elevated in pleural fluids of tuberculous pleuritis (TBP) where pleural mesothelial cells (PMCs) conduct the first-line defense against Mycobacterium tuberculosis (MTB). However, the clinical implication of TNF-α and MMPs in TBP and the response of PMCs to MTB infection remain unclear. METHODS: We measured pleural fluid levels of TNF-α and MMPs in patients with TBP (n = 18) or heart failure (n = 18) as controls. Radiological scores for initial effusion amount and residual pleural fibrosis at 6-month follow-up were assessed. In vitro human PMC experiments were performed to assess the effect of heat-killed M. tuberculosis H37Ra (MTBRa) on the expression of TNF-α and MMPs. RESULTS: As compared with controls, the effusion levels of TNF-α, MMP-1 and MMP-9 were significantly higher and correlated positively with initial effusion amount in patients with TBP, while TNF-α and MMP-1, but not MMP-9, were positively associated with residual pleural fibrosis of TBP. Moreover, effusion levels of TNF-α had positive correlation with those of MMP-1 and MMP-9 in TBP. In cultured PMCs, MTBRa enhanced TLR2 and TLR4 expression, activated ERK signaling, and upregulated TNF-α mRNA and protein expression. Furthermore, knockdown of TLR2, but not TLR4, significantly inhibited ERK phosphorylation and TNF-α expression. Additionally, both MTBRa and TNF-α markedly induced MMP-1 and MMP-9 synthesis in human PMCs, and TNF-α neutralization substantially reduced the production of MMP-1, but not MMP-9, in response to MTBRa stimulation. CONCLUSION: MTBRa activates TLR2/ERK signalings to induce TNF-α and elicit MMP-1 and MMP-9 in human PMCs, which are associated with effusion volume and pleural fibrosis and may contribute to pathogenesis of TBP. Further investigation of manipulation of TNF-α and MMP expression in pleural mesothelium may provide new insights into the mechanisms and rational treatment strategies for TBP.


Assuntos
Células Epiteliais/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 9 da Matriz/imunologia , Mycobacterium tuberculosis/imunologia , Receptor 2 Toll-Like/imunologia , Tuberculose Pulmonar/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Células Epiteliais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pleura/imunologia , Pleura/patologia , Tuberculose Pulmonar/patologia , Regulação para Cima/imunologia
20.
J Allergy Clin Immunol ; 135(3): 712-20, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25583101

RESUMO

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory disease. The prevalence of allergic contact dermatitis to allergens (eg, fragrance) is higher in patients with AD, despite a trend toward weaker clinical allergic contact dermatitis reactions. The role of the AD skin phenotype in modulating allergic sensitization to common sensitizers has not been evaluated. OBJECTIVE: We sought to investigate whether patients with AD have altered tissue immune responses on allergen challenge. METHODS: Gene expression and immunohistochemistry studies were performed on biopsy specimens from 10 patients with AD and 14 patients without AD patch tested with common contact allergens (nickel, fragrance, and rubber). RESULTS: Although 1085 differentially expressed genes (DEGs) were commonly modulated in patch-tested skin from patients with AD and patients without AD versus control skin, 1185 DEGs were uniquely altered in skin from patients without AD, and only 246 DEGs were altered in skin from patients with AD. Although many inflammatory products (ie, matrix metalloproteinase 12/matrix metalloproteinase 1/S100A9) were upregulated in both groups, higher-magnitude changes and upregulation of interferon responses were evident only in the non-AD group. Stratification by allergen showed decreased expression of immune, TH1-subset, and TH2-subset genes in nickel-related AD responses, with increased TH17/IL-23 skewing. Rubber/fragrance showed similar trends of lesser magnitude. Negative regulators showed higher expression in patients with AD. CONCLUSIONS: Through contact sensitization, our study offers new insights into AD. Allergic immune reactions were globally attenuated and differentially polarized in patients with AD, with significant decreases in levels of TH1 products, some increases in levels of TH17 products, and inconsistent upregulation in levels of TH2 products. The overall hyporesponsiveness in skin from patients with background AD might be explained by baseline immune abnormalities, such as increased TH2, TH17, and negative regulator levels compared with those seen in non-AD skin.


Assuntos
Alérgenos/imunologia , Citocinas/imunologia , Dermatite Atópica/imunologia , Dermatite de Contato/imunologia , Transcriptoma/imunologia , Adulto , Calgranulina B/genética , Calgranulina B/imunologia , Cosméticos/química , Citocinas/genética , Dermatite Atópica/patologia , Dermatite de Contato/patologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Látex/imunologia , Masculino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 12 da Matriz/imunologia , Pessoa de Meia-Idade , Níquel/imunologia , Testes do Emplastro , Borracha/química , Pele , Células Th1/imunologia , Células Th1/patologia , Células Th17/imunologia , Células Th17/patologia , Células Th2/imunologia , Células Th2/patologia
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