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1.
Cells ; 10(2)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672296

RESUMO

Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson's disease (PD) and contribute to sporadic PD. Common genetic variation in LRRK2 modifies susceptibility to immunological disorders including Crohn's disease and leprosy. Previous studies have reported that LRRK2 is expressed in B lymphocytes and macrophages, suggesting a role for LRRK2 in immunological functions. In this study, we characterized the LRRK2 protein expression and phosphorylation using human lymphoblasts. Lipopolysaccharide (LPS), a proinflammatory agent, induced the increase of LRRK2 expression and kinase activities in human lymphoblasts in a time-dependent manner. Moreover, LPS activated the Toll-like receptor (TLR) signaling pathway, increased TRAF6/LRRK2 interaction, and elevated the phosphorylation levels of MAPK (JNK1/2, p38, and ERK1/2) and IkBα. Treatment with LRRK2 inhibitor 68 reduced LPS-induced TRAF6/LRRK2 interaction and MAPK and IkBα phosphorylation, thereby reducing TNF-α secretion. These results indicate that LRRK2 is actively involved in proinflammatory responses in human lymphoblasts, and inhibition of GTP binding by 68 results in an anti-inflammation effect against proinflammatory stimuli. These findings not only provide novel insights into the mechanisms of LRRK2-linked immune and inflammatory responses in B-cell-like lymphoblasts, but also suggest that 68 may also have potential therapeutic value for LRRK2-linked immunological disorders.


Assuntos
Guanosina Trifosfato/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Lipopolissacarídeos/farmacologia , Linfócitos/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Humanos , Linfócitos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , Inibidor de NF-kappaB alfa/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Fator 6 Associado a Receptor de TNF/metabolismo
2.
J Leukoc Biol ; 110(1): 167-176, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33040382

RESUMO

The enzyme IDO-1 is involved in the first stage of tryptophan catabolism and has been described in both microbicidal and tolerogenic microenvironments. Previous data from our group have shown that IDO-1 is differentially regulated in the distinctive clinical forms of leprosy. The present study aims to investigate the mechanisms associated with IDO-1 expression and activity in human monocyte-derived dendritic cells (mDCs) after stimulation with irradiated Mycobacterium leprae and its fractions. M. leprae and its fractions induced the expression and activity of IDO-1 in human mDCs. Among the stimuli studied, irradiated M. leprae and its membrane fraction (MLMA) induced the production of proinflammatory cytokines TNF and IL-6 whereas irradiated M. leprae and its cytosol fraction (MLSA) induced an increase in IL-10. We investigated if TLR2 activation was necessary for IDO-1 induction in mDCs. We observed that in cultures treated with a neutralizing anti-TLR2 antibody, there was a decrease in IDO-1 activity and expression induced by M. leprae and MLMA. The same effect was observed when we used a MyD88 inhibitor. Our data demonstrate that coculture of mDCs with autologous lymphocytes induced an increase in regulatory T (Treg) cell frequency in MLSA-stimulated cultures, showing that M. leprae constituents may play opposite roles that may possibly be related to the dubious effect of IDO-1 in the different clinical forms of disease. Our data show that M. leprae and its fractions are able to differentially modulate the activity and functionality of IDO-1 in mDCs by a pathway that involves TLR2, suggesting that this enzyme may play an important role in leprosy immunopathogenesis.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Tolerância Imunológica , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Hanseníase/etiologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Receptor 2 Toll-Like/metabolismo , Biomarcadores , Citometria de Fluxo , Humanos , Hanseníase/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
J Oncol Pharm Pract ; 27(3): 673-678, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33249990

RESUMO

BACKGROUND: Thalidomide is the most teratogenic human medicine ever marketed and was associated with birth defects in approximately 10,000 children in the 1960s. The pharmacological effects of thalidomide are attributed to its anti-angiogenic, anti-inflammatory and modulatory effect on cytokines principally tumor necrosis factor-α, while the teratogenic effects are linked to two molecular targets, namely cereblon and tubulin. Teratogenicity is the gravest adverse effect of thalidomide depending on the dose and time of exposure. Nonetheless, with System for Thalidomide Education and Prescribing Safety program, the possibility of teratogenicity can be completely avoided. The sensitive period during pregnancy for thalidomide teratogenicity in humans is approximately 20-34 days after fertilization. METHODS: Relevant articles were identified from Google scholar and PubMed (MEDLINE) using different search strategies. CONCLUSION: Clinical trials showed that thalidomide has been found effective in the treatment of advanced renal cancer, esophageal cancer, chemotherapy refractory endometrial cancer and pancreatic cancer, which can suggest its future therapeutic potential in cancer treatment. Thalidomide is also used in the treatment of inflammatory skin disorders and has shown promising effect in the treatment of autoimmune disorders and inflammatory bowel disease. Despite thalidomide being a renowned teratogen and neurotoxin, it has been successfully repositioned and FDA approved for the treatment of erythema nodosum leprosum and multiple myeloma under strict control.


Assuntos
Reposicionamento de Medicamentos/métodos , Imunossupressores/administração & dosagem , Teratógenos , Talidomida/administração & dosagem , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Reposicionamento de Medicamentos/tendências , Feminino , Humanos , Recém-Nascido , Neoplasias Renais/diagnóstico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Gravidez , Talidomida/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
4.
Cancer Chemother Pharmacol ; 85(3): 563-571, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31915967

RESUMO

PURPOSE: It has been supposed that cardiac toxicity of doxorubicin is due to its production of free radicals and inflammatory cytokines. Dapsone, an antibiotic drug which is the principal in a multidrug regimen for the treatment of leprosy, is a sulfone with anti-inflammatory and antioxidant immunosuppressive properties. Therefore, we designed this study to investigate the possible effects of dapsone on doxorubicin-induced cardiotoxicity. METHODS: Male rats were administrated doxorubicin (2.5 mg/kg) and dapsone (1, 3, 10 mg/kg) intraperitoneally six times in 2 weeks. Then electrocardiographic (ECG) parameters (QRS complexes, RR and QT intervals) alternation, papillary muscle contraction and excitation, and histopathological changes were assessed. Also, the heart tissue levels of malondialdehyde (MDA) as oxidant factor and superoxide dismutase (SOD) as antioxidant enzyme, tumor necrosis factor-alpha (TNF-α) and serum level of CK-MB were analyzed. RESULTS: Administration of dapsone with doxorubicin significantly reversed alterations induced by doxorubicin in serum levels of CK-MB, ECG parameters, papillary muscle contractility and excitation. Furthermore, the measurement of MDA, SOD and TNF-α tissue level indicated that dapsone significantly reduced oxidative stress and inflammation. These findings were consistent with histopathological analysis. CONCLUSION: Dapsone exerts cardioprotective effects on doxorubicin-induced cardiotoxicity through its anti-inflammatory and antioxidant mechanism.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Dapsona/farmacologia , Doxorrubicina/efeitos adversos , Coração/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
5.
J Vet Sci ; 19(6): 744-749, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30304888

RESUMO

Dapsone, an antibiotic, has been used to cure leprosy. It has been reported that dapsone has anti-inflammatory activity in hosts; however, the anti-inflammatory mechanism of dapsone has not been fully elucidated. The present study investigated the anti-inflammatory effects of dapsone on bone marrow cells (BMs), especially upon exposure to lipopolysaccharide (LPS). We treated BMs with LPS and dapsone, and the treated cells underwent cellular activity assay, flow cytometry analysis, cytokine production assessment, and reactive oxygen species assay. LPS distinctly activated BMs with several characteristics including high cellular activity, granulocyte changes, and tumor necrosis factor alpha (TNF-α) production increases. Interestingly, dapsone modulated the inflammatory cells, including granulocytes in LPS-treated BMs, by inducing cell death. While the percentage of Gr-1 positive cells was 57% in control cells, LPS increased that to 75%, and LPS plus dapsone decreased it to 64%. Furthermore, dapsone decreased the mitochondrial membrane potential of LPS-treated BMs. At a low concentration (25 µg/mL), dapsone significantly decreased the production of TNF-α in LPS-treated BMs by 54%. This study confirmed that dapsone has anti-inflammatory effects on LPS-mediated inflammation via modulation of the number and function of inflammatory cells, providing new and useful information for clinicians and researchers.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Dapsona/farmacologia , Lipopolissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células da Medula Óssea/metabolismo , Regulação para Baixo/efeitos dos fármacos , Citometria de Fluxo , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo
6.
J Ethnopharmacol ; 219: 222-232, 2018 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-29530609

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Sesbania grandiflora (Linn) belonging to the family Fabaceae is commonly known as sesbania, agathi, and katurai. The plant is accredited for alleviating a spectrum of ailments including inflammation, colitis, diarrhea, dysentery, leprosy, gout, rheumatism, jaundice, bronchitis, convulsion and anxiety. It is also used as antitumour, anthelmintic, and laxatives in Ayurveda and Siddha system of Indian traditional medicine. AIM: To reveal protective effect of Sesbania grandiflora in acetic acid induced ulcerative colitis in mice. MATERIALS AND METHOD: Polyphenol, flavonoid and flavanone contents of different extracts of S. grandiflora leaves were quantified and correlated with their antioxidant capacity in-vitro (DPPH assay) for identification of potential fraction. In further studies hydroalocholic extract (HASG, 100 and 200 mg/kg) was evaluated for protective effect towards acetic acid induced ulcerative colitis (UC) animals administered with 150 µl of 5% acetic acid once, intrarectally. The colonic mucosal injury was assessed by estimating disease activity index (DAI), which took into account weight loss, stool consistency and occult/gross bleeding. Macroscopic changes like colon length, spleen weights, ulcer area and ulcer index were determined. Haematological parameters like WBC count, RBC count, Hb (g/dL), HCT (%), PLT count and FFA level were determined. Biochemical analysis was carried out for asserting the levels of tissue myeloperoxidase (MPO) accumulation, SOD concentrations, reduced GSH and lipid peroxidation in UC induced and treated animals. The cardinal inflammatory biomarkers like nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin (IL-6) were determined. Histopathological investigation was carried out and scores were calculated. RESULTS: HASG showed presence of highly polymerized polyphenols and flavonoids amongst other extracts of S. grandiflora, which is correlated to its rich antioxidant potential (IC50 =19.21). HPLC fingerprinting quantifies the presence of quercetin in concentration of 81.7 µg/mg of HASG. HASG (200 mg/kg) and Prednisolone (2 mg/kg) significantly reduced DAI and macroscopic scores. The haematological changes in experimental animals were restored upon treatment with HASG and Prednisolone. HASG showed potent antioxidant activity (In-vivo) by restoring the levels of SOD, GSH, MPO, MDA and NO. HASG was found to inhibit FFA levels, which may indicate inhibition of TLR4 receptor mediated inflammation. The levels of serological biomarkers like TNF-α and IL-6 were found to be suppressed. Histopathological investigation reveals decrease signs of ulceration, necrosis, cellular infiltration, hyperaemia in HASG treated animals. The results of HASG (200 mg/kg) were found to be comparable with Prednisolone (2 mg/kg) significantly. CONCLUSION: The protective action of HASG against acetic acid induced UC is attributed to the antioxidant like action (In-vitro and In-vivo) of highly polymerized polyphenols and flavonoids especially quercetin. Also HASG was found to reduce the levels of TNF-α and IL-6, thereby suppressing their inflammatory response in UC.


Assuntos
Ácido Acético/toxicidade , Colite Ulcerativa/prevenção & controle , Interleucina-6/antagonistas & inibidores , Extratos Vegetais/uso terapêutico , Sesbania , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
7.
Int J Mycobacteriol ; 5(2): 223-5, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27242236

RESUMO

Erythema nodosum leprosum (ENL) is a common complication of lepromatous leprosy. Some patients unresponsive to conventional, first-line therapeutics develop recurrent, recalcitrant ENL. Here, we report a case of severe refractory ENL that was successfully treated with Etanercept. Biologics may be considered as therapeutic alternatives in management of severe, recalcitrant ENL.


Assuntos
Eritema Nodoso/tratamento farmacológico , Etanercepte/administração & dosagem , Hanseníase/complicações , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Eritema Nodoso/etiologia , Eritema Nodoso/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo
8.
Antimicrob Agents Chemother ; 60(6): 3470-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27021320

RESUMO

Clofazimine (CFZ) is a poorly soluble antibiotic and anti-inflammatory drug indicated for the treatment of leprosy. In spite of its therapeutic value, CFZ therapy is accompanied by the formation of drug biocrystals that accumulate within resident tissue macrophages, without obvious toxicological manifestations. Therefore, to specifically elucidate the off-target consequences of drug bioaccumulation in macrophages, we compared the level of inflammasome activation in CFZ-accumulating organs (spleen, liver and lung) in mice after 2 and 8 weeks of CFZ treatment when the drug exists in soluble and insoluble (biocrystalline) forms, respectively. Surprisingly, the results showed a drastic reduction in caspase 1 and interleukin-1ß (IL-1ß) cleavage in the livers of mice treated with CFZ for 8 weeks (8-week-CFZ-treated mice) compared to 2-week-CFZ-treated and control mice, which was accompanied by a 3-fold increase in hepatic IL-1 receptor antagonist (IL-1RA) production and a 21-fold increase in serum IL-1RA levels. In the lung and spleen, IL-1ß cleavage and tumor necrosis factor alpha expression were unaffected by soluble or biocrystal CFZ forms. Functionally, there was a drastic reduction of carrageenan- and lipopolysaccharide-induced inflammation in the footpads and lungs, respectively, of 8-week-CFZ-treated mice. This immunomodulatory activity of CFZ biocrystal accumulation was attributable to the upregulation of IL-1RA, since CFZ accumulation had minimal effect in IL-1RA knockout mice or 2-week-CFZ-treated mice. In conclusion, CFZ accumulation and biocrystal formation in resident tissue macrophages profoundly altered the host's immune system and prompted an IL-1RA-dependent, systemic anti-inflammatory response.


Assuntos
Anti-Inflamatórios/farmacologia , Clofazimina/farmacologia , Inflamassomos/imunologia , Proteína Acessória do Receptor de Interleucina-1/biossíntese , Macrófagos/efeitos dos fármacos , Animais , Carragenina , Caspase 1/metabolismo , Inflamação/tratamento farmacológico , Proteína Acessória do Receptor de Interleucina-1/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Fígado/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Baço/metabolismo , Ativação Transcricional/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
9.
Mediators Inflamm ; 2015: 548540, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26339136

RESUMO

Reactional episodes in leprosy are a result of complex interactions between the immune system, Mycobacterium leprae, and predisposing factors, including dental infections. To determine the main inflammatory mediators in the immunopathological process of dental infections and leprosy reactions, we conducted a systematic review of primary literature published between 1996 and 2013. A three-stage literature search was performed (Stage I, "leprosy reactions" and "inflammatory mediators"; Stage II, "dental infections" and "inflammatory mediators"; and Stage III, "leprosy reactions," "dental infections," and "inflammatory mediators"). Of the 911 eligible publications, 10 were selected in Stage I, 68 in Stage II, and 1 in Stage III. Of the 27 studied inflammatory mediators, the main proinflammatory mediators were IL-6, IFN-γ, TNF-α, IL-1ß, and IL-17; the main anti-inflammatory mediators were IL-10 and IL-4. Serum IL-6 and TNF-α concentrations were significant during periodontal and reactional lesion evolution; IFN-γ and IL-1ß were associated with types 1 and 2 reactions and chronic periodontal disease. The proinflammatory mediators in dental infections and leprosy reactions, especially IL-6 and TNF-α, were similar across studies, regardless of the laboratory technique and sample type. IFN-γ and IL-1ß were significant for leprosy reactions and periodontal diseases. This pattern was maintained in serum.


Assuntos
Citocinas/metabolismo , Hanseníase/imunologia , Doenças Estomatognáticas/imunologia , Animais , Humanos , Interferon gama/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Mycoses ; 58(9): 522-30, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26156007

RESUMO

There are no studies investigating the role of nutritional status and immunity associated with Jorge Lobo's disease. The objective of this study was to evaluate the effects of protein-calorie malnutrition on the immune response of BALB/c mice inoculated with Lacazia loboi. In this study,the animals were divided into four groups: G1: inoculated with restricted diet, G2: not inoculated with restricted diet, G3: inoculated with regular diet, G4: not inoculated with regular diet. The animals of groups G1 and G2 were submitted to malnutrition for 20 days and once installed the animals were inoculated intradermally into the footpad. After 4 months, they were euthanised for the isolation of peritoneal lavage cells and removal of the footpad. The production of IL-2, IL-4, IL-10, IL-12, IFN-γ, TNF-α, H2 O2 and nitric oxide (NO) was evaluated in the peritoneal lavage cells. The footpad was evaluated regarding the size of macroscopic lesions, number of fungi and viability index. The results showed that the infection did not exert great influence on the body weight of the mice and previous malnutrition was an unfavourable factor for viability index, number of fungi, macroscopic lesion size in the footpad and production of H2 O2 , NO, IL-12, IL-10 and IFN-γ, suggesting that malnutrition significantly altered fungal activity and peritoneal cells. The results suggest considerable interaction between nutrition and immunity in Jorge Lobo's disease.


Assuntos
Lacazia , Lobomicose/imunologia , Lobomicose/microbiologia , Desnutrição/complicações , Estado Nutricional , Animais , Peso Corporal , Citocinas/metabolismo , Modelos Animais de Doenças , Interleucina-12/metabolismo , Interleucina-2/metabolismo , Lacazia/imunologia , Lobomicose/complicações , Camundongos , Camundongos Endogâmicos BALB C , Lavagem Peritoneal , Peritônio/citologia , Peritônio/imunologia , Fator de Necrose Tumoral alfa/metabolismo
11.
J Infect ; 71(4): 413-21, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26092350

RESUMO

Melanin is a canonical and major defense molecule in invertebrates but its role in mammalian immunity remains unexplored. In contrast, several recent studies have highlighted the emerging innate immune activities of human melanin-producing cells which can sense and respond to bacterial and viral infections. Indeed, the skin is a major portal of entry for pathogens such as arboviruses (Chikungunya, Dengue) and bacteria (mycobacterium leprae, Leptospira spirochetes). Melanocytes of the epidermis could contribute to the phagocytosis of these invading pathogens and to present antigens to competent immune cells. Melanocytes are known to produce key cytokines such as IL-1ß, IL6 and TNF-α as well as chemokines. These molecules will subsequently alert macrophages, neutrophils, fibroblasts and keratinocytes through unique crosstalk mechanisms. The infection and the inflammatory responses will control melanocyte's immune and metabolic functions and could contribute to skin manifestations (rash, hyper or de-pigmentation, epidermolysis and psoriasis-like lesions). This review will address the potential role of melanocytes in immunity, inflammation and infection of the skin in health and diseases.


Assuntos
Infecções Bacterianas/imunologia , Dengue/imunologia , Inflamação/imunologia , Melanócitos/imunologia , Infecções Bacterianas/microbiologia , Infecções Bacterianas/prevenção & controle , Citocinas/biossíntese , Citocinas/metabolismo , Dengue/prevenção & controle , Dengue/virologia , Humanos , Imunidade Inata , Melanócitos/metabolismo , Melanócitos/ultraestrutura , Pele/imunologia , Fator de Necrose Tumoral alfa/metabolismo
12.
Cell Physiol Biochem ; 35(4): 1276-88, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25721573

RESUMO

BACKGROUND: The early secreted antigenic target 6-kDa protein (ESAT-6) of Mycobacterium tuberculosis (Mtb) not only acts as a key player for virulence but also exhibits a strong immunotherapeutic potential against Mtb. However, little is known about the molecular basis for its potential in immunotherapy. The present study was designed to unravel the role of miRNA-155 in ESAT-6-mediated enhancement of host immunity and apoptosis in macrophages. METHODS: Lentivirus-mediated miR-155 sponge and miR-155 and SOCS1 overexpression vectors were developed in macrophages. TLR2- or p65-specific siRNA knockdown was employed to silence TLR2 or p65. Quantitative polymerase chain reaction and western blotting analyses were performed to determine mRNA and protein expression levels, respectively. Macrophage apoptosis was analyzed by flow cytometry. RESULTS: ESAT-6 significantly increased miR-155 expression, which was dependent on TLR2/NF-κB activation in macrophages. Induced expression of miRNA-155 was required for the ESAT-6-mediated protective immune response and macrophage apoptosis. ESAT-6 promoted macrophage apoptosis by targeting the miR-155-SOCS1 pathway. The differential expression levels of TLR2, BIC, and SOCS1 were involved in regulating the immune response in human peripheral blood mononuclear cells of patients with active tuberculosis (TB) and latent TB (LTB). CONCLUSION: ESAT-6 promotes apoptosis of macrophages via targeting the miRNA155-SOCS1 interaction.


Assuntos
Antígenos de Bactérias/farmacologia , Apoptose/efeitos dos fármacos , MicroRNAs/metabolismo , Mycobacterium tuberculosis/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Tuberculose/patologia , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Linhagem Celular , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Interferência de RNA , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Proteínas Supressoras da Sinalização de Citocina/genética , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Tuberculose/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
s.l; s.n; 2015. 15 p. ilus, tab.
Não convencional em Inglês | SES-SP, HANSEN, SESSP-ILSLPROD, SES-SP, SESSP-ILSLACERVO, SES-SP | ID: biblio-1095297

RESUMO

Reactional episodes in leprosy are a result of complex interactions between the immune system, Mycobacterium leprae, and predisposing factors, including dental infections. To determine the main inflammatory mediators in the immunopathological process of dental infections and leprosy reactions, we conducted a systematic review of primary literature published between 1996 and 2013. A three-stage literature search was performed (Stage I, "leprosy reactions" and "inflammatory mediators"; Stage II, "dental infections" and "inflammatory mediators"; and Stage III, "leprosy reactions," "dental infections," and "inflammatory mediators"). Of the 911 eligible publications, 10 were selected in Stage I, 68 in Stage II, and 1 in Stage III. Of the 27 studied inflammatory mediators, the main proinflammatory mediators were IL-6, IFN-γ, TNF-α, IL-1ß, and IL-17; the main anti-inflammatory mediators were IL-10 and IL-4. Serum IL-6 and TNF-α concentrations were significant during periodontal and reactional lesion evolution; IFN-γ and IL-1ß were associated with types 1 and 2 reactions and chronic periodontal disease. The proinflammatory mediators in dental infections and leprosy reactions, especially IL-6 and TNF-α, were similar across studies, regardless of the laboratory technique and sample type. IFN-γ and IL-1ß were significant for leprosy reactions and periodontal diseases. This pattern was maintained in serum.


Assuntos
Humanos , Animais , Doenças Estomatognáticas/imunologia , Citocinas/metabolismo , Interferon gama/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Hanseníase/imunologia
15.
Infect Immun ; 80(10): 3512-20, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22851747

RESUMO

SecA2 is an ATPase present in some pathogenic Gram-positive bacteria, is required for translocation of a limited set of proteins across the cytosolic membrane, and plays an important role in virulence in several bacteria, including mycobacteria that cause diseases such as tuberculosis and leprosy. However, the mechanisms by which SecA2 affects virulence are incompletely understood. To investigate whether SecA2 modulates host immune responses in vivo, we studied Mycobacterium marinum infection in two different hosts: an established zebrafish model and a recently described mouse model. Here we show that M. marinum ΔsecA2 was attenuated for virulence in both host species and SecA2 was needed for normal granuloma numbers and for optimal tumor necrosis factor alpha response in both zebrafish and mice. M. marinum ΔsecA2 was more sensitive to SDS and had unique protrusions from its cell envelope when examined by cryo-electron tomography, suggesting that SecA2 is important for bacterial cell wall integrity. These results provide evidence that SecA2 induces granulomas and is required for bacterial modulation of the host response because it affects the mycobacterial cell envelope.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Bactérias/metabolismo , Granuloma/microbiologia , Proteínas de Membrana Transportadoras/metabolismo , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium marinum/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adenosina Trifosfatases/genética , Animais , Proteínas de Bactérias/genética , Células Cultivadas , Feminino , Humanos , Inflamação/metabolismo , Macrófagos , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/metabolismo , Mycobacterium marinum/genética , Mycobacterium marinum/patogenicidade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/genética , Virulência , Peixe-Zebra
16.
Curr Top Med Chem ; 12(13): 1436-55, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22650376

RESUMO

Thalidomide and its one analogue, lenalidomide (CC5103 or revlimid) are recently approved for the treatment of multiple myeloma. Multiple myeloma is characterized by an overproduction of malignant plasma cells in the bone marrow. The journey of thalidomide was started in 1956 when it was marketed as a non-barbiturate sedative agent. It was considered as a "wonder drug" that provided safe and sound sleep and hence, used to cure morning sickness in pregnant women. Later, in 1961, it was withdrawn from the world market due to its serious side effects, i.e., teratogenic activity. However, the recent decade has witnessed a true renaissance in interest in its broad biological activity. In particular, thalidomide was reevaluated and attracted significant attention due to its selective inhibitory activity of tumor necrosis factor-α (TNF-α), which is a clinically important activity against serious diseases such as rheumatoid arthritis, Crohn's disease, leprosy, AIDS, and various cancers. The comeback of thalidomide to the legitimate status of a marketed drug came in 1998 when it received FDA approval for the treatment of erythema nodosum leprosum (ENL). Recently, the drug has got FDA approval for the treatment of multiple myeloma. In the last few years, number of thalidomide analogues have been synthesized and are in clinical development as a class of immunomodulatory drugs. Among these, lenalidomide is more potent than thalidomide, and is also non-neurotoxic. It was shown in vitro studies to induce apoptosis or arrest growth even in resistant multiple myeloma cell lines, decrease binding of the cells to bone marrow stromal cells, and stimulate host natural killer cell immunity. It also inhibits tumour growth and decreases angiogenesis. Earlier reviews have described the pharmacological aspects of thalidomide and a review has focused only on synthetic aspect of thalidomide. However, review focusing on chemistry and metabolism and mechanism of biological activity is still lacking. In this review, we will concisely describe the therapeutic aspects, metabolism and synthesis of thalidomide.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Teratógenos/farmacologia , Talidomida/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Humanos , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Teratógenos/química , Teratógenos/metabolismo , Talidomida/efeitos adversos , Talidomida/química , Talidomida/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
17.
Microbes Infect ; 14(4): 348-56, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22138502

RESUMO

Despite the popular belief that granulomas are innate immune mechanism to restrict mycobacterial growth, evidences suggest that granulomas facilitate growth of Mycobacterium by recruiting large numbers of uninfected macrophages to the site of infection. Matrix metalloproteinase-9 (MMP-9) has been shown to be directly involved in recruitment of macrophages at the site of infection, contributing to nascent granuloma maturation and bacterial growth. In this manuscript it is reported that heat-killed Mycobacterium indicus pranii (MIP) leads to a significant downregulation of MMP-9 in murine peritoneal macrophages in vitro. The downregulation of MMP-9 is mediated through cyclooxygenase-2 (COX-2), but independent of tumor necrosis factor-α (TNF-α). By limiting nuclear to cytoplasmic export of COX-2 and iNOS transcripts, MIP inhibits excessively-high levels of nitric oxide which can be damaging to the host during acute phases of infection. MIP has been shown to provide clinical improvement in all phases of leprosy and used for treatment of leprosy and tuberculosis.


Assuntos
Ciclo-Oxigenase 2/genética , Macrófagos Peritoneais/enzimologia , Metaloproteinase 9 da Matriz/genética , Mycobacterium/fisiologia , Óxido Nítrico Sintase Tipo II/genética , Fator de Necrose Tumoral alfa/genética , Animais , Arginina/metabolismo , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Feminino , Expressão Gênica , Regulação da Expressão Gênica/imunologia , Macrófagos Peritoneais/imunologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Transporte de RNA/imunologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
18.
PLoS Negl Trop Dis ; 5(12): e1327, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22180790

RESUMO

BACKGROUND: Previous studies investigating the role of cytokines in the pathogenesis of leprosy have either been on only small numbers of patients or have not combined clinical and histological data. The INFIR Cohort study is a prospective study of 303 new multibacillary leprosy patients to identify risk factors for reaction and nerve damage. This study characterised the cellular infiltrate in skin and nerve biopsies using light microscopic and immunohistochemical techniques to identify any association of cytokine markers, nerve and cell markers with leprosy reactions. METHODOLOGY/PRINCIPAL FINDINGS: TNF-α, TGF-ß and iNOS protein in skin and nerve biopsies were detected using monoclonal antibody detection immunohistochemistry techniques in 299 skin biopsies and 68 nerve biopsies taken from patients at recruitment. The tissues were stained with hematoxylin and eosin, modified Fite Faraco, CD68 macrophage cell marker and S100. CONCLUSIONS/SIGNIFICANCE: Histological analysis of the biopsies showed that 43% had borderline tuberculoid (BT) leprosy, 27% borderline lepromatous leprosy, 9% lepromatous leprosy, 13% indeterminate leprosy types and 7% had no inflammation. Forty-six percent had histological evidence of a Type 1 Reaction (T1R) and 10% of Erythema Nodosum Leprosum. TNF-α was detected in 78% of skin biopsies (181/232), iNOS in 78% and TGF-ß in 94%. All three molecules were detected at higher levels in patients with BT leprosy. TNF-α was localised within macrophages and epithelioid cells in the granuloma, in the epidermis and in dermal nerves in a few cases. TNF-α, iNOS and TGF-ß were all significantly associated with T1R (p<0.001). Sixty-eight nerve biopsies were analysed. CD68, TNF-α and iNOS staining were detectable in 88%, 38% and 28% of the biopsies respectively. The three cytokines TNF-α, iNOS and TGF-ß detected by immunohistochemistry showed a significant association with the presence of skin reaction. This study is the first to demonstrate an association of iNOS and TGF-ß with T1R.


Assuntos
Citocinas/metabolismo , Hanseníase/metabolismo , Biomarcadores/metabolismo , Biópsia , Estudos de Coortes , Humanos , Imuno-Histoquímica , Índia , Hanseníase/imunologia , Hanseníase/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Nervos Periféricos/imunologia , Nervos Periféricos/metabolismo , Reprodutibilidade dos Testes , Pele/imunologia , Pele/metabolismo , Pele/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Lepr Rev ; 82(1): 25-35, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21644469

RESUMO

OBJECTIVE: We investigated the in vitro and skin lesions production of cytokines in non-treated borderline tuberculoid (BT) and borderline lepromatous (BL) patients. PATIENTS AND METHODS: Seven untreated, non-reactional BT patients and 12 untreated, non-reactional BL patients were studied. Levels of the cytokines IFN-gamma, IL-10, TGF-beta1 and TNF-alpha were measured in supernantant of peripheral blood mononuclear cells (PBMC) cultures, stimulated with specific M. leprae antigen (sonicated and whole). The cytokines iNOS, IL-10 and TGF-beta1 were detected by immunohistochemistry in skin biopsies. RESULTS: BT patients produced higher levels of IFN-gamma than BL patients; iNOS expression in skin lesions was also higher in BT patients. TGF-beta1 was detected in more cells in BL patients; IL-10 expression was similar in both groups. There was a negative correlation between iNOS and TGF-beta1 expression in skin biopsies, positive correlation between TGF-beta1 in skin lesions and bacillary index, as well as positive correlation between iNOS detected in skin biopsies and PBMC IFN-gamma production. CONCLUSIONS: The BT patients had a mainly a Th1-profile of cytokines in their skin lesions and BL patients had a Th2 profile.


Assuntos
Citocinas/metabolismo , Hanseníase Dimorfa/metabolismo , Hanseníase Virchowiana/metabolismo , Hanseníase Tuberculoide/metabolismo , Biomarcadores/metabolismo , Biópsia , Brasil/epidemiologia , Feminino , Humanos , Imuno-Histoquímica , Interferon gama/metabolismo , Interleucina-10/metabolismo , Hanseníase Dimorfa/epidemiologia , Hanseníase Virchowiana/epidemiologia , Hanseníase Tuberculoide/epidemiologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/metabolismo , Estatísticas não Paramétricas , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
J Neuropathol Exp Neurol ; 69(1): 27-39, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20010305

RESUMO

Matrix metalloproteinases (MMPs) mediate demyelination and breakdown of the blood-nerve barrier in peripheral neuropathies. Matrix metalloproteinases and tissue inhibitor of metalloproteinase 1 gene expression and secretion were studied in cells of the human Schwann cell line ST88-14 stimulated with Mycobacterium leprae and tumor necrosis factor (TNF) and in nerve biopsies from patients with neural leprosy (n = 21) and nonleprous controls (n = 3). Mycobacterium leprae and TNF induced upregulation of MMP-2 and MMP-9 and increased secretion of these enzymes in cultured ST88-14 cells. The effects of TNF and M. leprae were synergistic, and anti-TNF antibody blockage partially inhibited this synergistic effect. Nerves with inflammatory infiltrates and fibrosis displayed higher TNF, MMP-2, and MMP-9 mRNA than controls. Leprous nerve biopsies with no inflammatory alterations also exhibited higher MMP-2 and MMP-9; tissue inhibitor of metalloproteinase 1 was significantly higher in biopsies with fibrosis and inflammation. Immunohistochemical double labeling of the nerves demonstrated that the MMPs were mainly expressed by macrophages and Schwann cells. The biopsies with endoneurial inflammatory infiltrates and epithelioid granulomas had the highest levels of MMP-2 and MMP-9 mRNA detected. Together, these results suggest that M. leprae and TNF may directly induce Schwann cells to upregulate and secrete MMPs regardless of the extent of inflammation in leprous neuropathy.


Assuntos
Hanseníase/etiologia , Hanseníase/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Mycobacterium leprae/fisiologia , Doenças do Sistema Nervoso Periférico/enzimologia , Células de Schwann/enzimologia , Adulto , Análise de Variância , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Neurilemoma/patologia , Doenças do Sistema Nervoso Periférico/microbiologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/fisiologia
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