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1.
Adv Exp Med Biol ; 1223: 81-97, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030686

RESUMO

The involvement of inflammation in cancer progression is well-established. The immune system can play both tumor-promoting and -suppressive roles, and efforts to harness the immune system to help fight tumor growth are at the forefront of research. Of particular importance is the inflammatory profile at the site of the tumor, with respect to both the leukocyte population numbers, the phenotype of these cells, as well as the contribution of the tumor cells themselves. In this regard, the pro-inflammatory effects of pattern recognition receptor expression and activation in the tumor microenvironment have emerged as a relevant issue both for therapy and to understand tumor development.Pattern recognition receptors (PRRs) were originally recognized as components of immune cells, particularly innate immune cells, as detectors of pathogens. PRR signaling in immune cells activates them, inducing robust antimicrobial responses. In particular, toll-like receptors (TLRs) constitute a family of membrane-bound PRRs which can recognize pathogen-associated molecular patterns (PAMPs) carried by bacteria, virus, and fungi. In addition, PRRs can recognize products generated by stressed cells or damaged tissues, namely damage-associated molecular patterns or DAMPS. Taking into account the role of the immune system in fighting tumors together with the presence of immune cells in the microenvironment of different types of tumors, strategies to activate immune cells via PRR ligands have been envisioned as an anticancer therapeutic approach.In the last decades, it has been determined that PRRs are present and functional on nonimmune cells and that their activation in these cells contributes to the inflammation in the tumor microenvironment. Both tumor-promoting and antitumor effects have been observed when tumor cell PRRs are activated. This argues against nonspecific activation of PRR ligands in the tumor microenvironment as a therapeutic approach. Therefore, the use of PRR ligands for anticancer therapy might benefit from strategies that specifically deliver these ligands to immune cells, thus avoiding tumor cells in some settings. This review focuses on these aspects of TLR signaling in the tumor microenvironment.


Assuntos
Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Microambiente Tumoral , Humanos , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Microambiente Tumoral/imunologia
2.
J Photochem Photobiol B ; 201: 111657, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31706085

RESUMO

Parkinson's disease (PD) is a general neurodegenerative disorder which largely has an effect on the society of the aged populations. PD is distinguishedwith loss of dopaminergic (DA) neurons in the substantia nigra. The exceptional properties of gold nanoparticles (AuNPs) have fascinated great attention in biomedical applications. In this present study, we explored theprospective beneficial effects of AuNPs synthesized from Cinnamomum verum on PD. PD rat models were established through MPTP injection treatment and AuNPs was administered. Administration of AuNPs reduces effect of MPTP-induced oxidative stress and motor abnormalities observed in PD rats. In addition ELISA analysis demonstrated that AuNPs treatment significantly attenuates Tumor Necrosis Factor-α (TNF-α), Interleukin-1ß (IL-1ß) and Interleukin-6 (IL-6) expression levels. Consequently, we investigated TLR/NF-κB pathway to examine the function of AuNPs on MPTP- induced PD rats. We found that AuNPs suppressed the alterations in the pathway of TLR/NF-κB associated molecules in MPTP stimulated PD rats. Hence, our results suggest that AuNPs attenuates MPTP introduced motor disorders, oxidative stress, activated inflammatory cytokines and activated TLR/NF-κB signaling in PD rats. In conclusion, AuNPs ease PD symptoms by the inhibition of TLR/NF-κB signaling pathway and recommend promise approach in the treatment of neurodegenerative diseases such as PD.


Assuntos
Cinnamomum zeylanicum/química , Ouro/química , Intoxicação por MPTP/tratamento farmacológico , Nanopartículas Metálicas/uso terapêutico , Animais , Cinnamomum zeylanicum/metabolismo , Citocinas/metabolismo , Química Verde , Intoxicação por MPTP/patologia , Masculino , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/metabolismo
3.
Semin Oncol ; 46(4-5): 385-392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31739997

RESUMO

There is no doubt that immunotherapy lies in the spotlight of current cancer research and clinical trials. However, there are still limitations in the treatment response in certain types of tumors largely due to the presence of the complex network of immunomodulatory and immunosuppressive pathways. These limitations are not likely to be overcome by current immunotherapeutic options, which often target isolated steps in immune pathways preferentially involved in adaptive immunity. Recently, we have developed an innovative anti-cancer immunotherapeutic strategy that initially elicits a strong innate immune response with subsequent activation of adaptive immunity in mouse models. Robust primary innate immune response against tumor cells is induced by toll-like receptor ligands and anti-CD40 agonistic antibodies combined with the phagocytosis-stimulating ligand mannan, anchored to a tumor cell membrane by biocompatible anchor for membrane. This immunotherapeutic approach results in a dramatic therapeutic response in large established murine subcutaneous tumors including melanoma, sarcoma, pancreatic adenocarcinoma, and pheochromocytoma. Additionally, eradication of metastases and/or long-lasting resistance to subsequent re-challenge with tumor cells was also accomplished. Current and future advantages of this immunotherapeutic approach and its possible combinations with other available therapies are discussed in this review.


Assuntos
Imunoterapia , Neoplasias/terapia , Imunidade Adaptativa , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Terapia Combinada , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade Inata , Imunomodulação , Imunoterapia/métodos , Ligantes , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Receptores Toll-Like/metabolismo , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
4.
Clin Exp Rheumatol ; 37 Suppl 120(5): 48-56, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621566

RESUMO

Osteoarthritis (OA) is the most common age-related chronic and disabling joint disease. Long considered to be a "wear and tear" disease, OA is now seen as a low-grade inflammation disease that affects all tissues of the joint, involving cartilage degradation, bone remodelling, osteophytes, and synovitis. The process, called inflammaging, is characterised by the association of low-grade inflammation, profound changes in intra-cellular mechanisms, and the decreased efficiency of the immune system with ageing. The activation of innate immunity plays a critical role in the development and progression of OA. Innate immunity, including inflammasome activation, is triggered by small endogenous molecules called alarmins or damage-associated molecular patterns (DAMPs). These molecules are released in the extracellular media after cell stress or damage, bind to pathogen-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE), and activate the secretion of pro-inflammatory factors, leading to joint inflammation. Moreover, such sterile inflammation triggers cell senescence, characterised by a senescence-associated secretory phenotype (SASP). Understanding the substantial age-related changes of joint tissues that influence the pathogenesis of OA is critical to improving the quality of life of elderly people in the context of increased life expectancy. This review will focus on age-related sterile inflammation in OA and highlight the various innovative and promising therapies targeting the mechanisms of aging.


Assuntos
Osteoartrite , Qualidade de Vida , Idoso , Envelhecimento , Humanos , Inflamação/imunologia , Osteoartrite/imunologia , Osteoartrite/patologia , Osteoartrite/terapia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptores Toll-Like/metabolismo
5.
J Microbiol Biotechnol ; 29(10): 1506-1521, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31581380

RESUMO

Tuberculosis, which is caused by Mycobacterium tuberculosis (Mtb), is among the most pressing worldwide problems. Mtb uniquely interacts with innate immune cells through various pattern recognition receptors. These interactions initiate several inflammatory pathways that play essential roles in controlling Mtb pathogenesis. Although the TLR signaling pathways have essential roles in numerous host's immune defense responses, the role of TLR signaling in the response to Mtb infection is still unclear. This review presents discussions on host-Mtb interactions in terms of Mtb-mediated TLR signaling. In addition, we highlight recent discoveries pertaining to these pathways that may help in new immunotherapeutic opportunities.


Assuntos
Mycobacterium tuberculosis/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Tuberculose/imunologia , Animais , Citocinas/metabolismo , Humanos , Imunidade Inata , Imunoterapia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/metabolismo , Tuberculose/terapia
6.
Mol Immunol ; 116: 56-62, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31605961

RESUMO

Macrophages can be polarized towards either a classically activated pro-inflammatory (M1) state, or alternatively towards an activated anti-inflammatory (M2) state. M1 cells are activated by ligands of toll-like receptor (TLR) or interferon (IFN)-γ and have a toxic effect, whereas M2 cells are activated by interleukin (IL)-4, IL-10, and IL-13 and have a regenerative effect in vitro and in vivo. Previously studies have shown that these cells play an important role in the inflammatory responses following spinal cord injury (SCI). Mechanistically, the role of PTEN in the regulation of macrophage polarization has yet to be fully elucidated. In the present study, we first evaluated the expression of PTEN in macrophages after SCI. We found that PTEN expression was accumulated in the macrophages after the SCI surgery. Knock-down of PTEN or inhibition of phospho-PTEN with bpV(pic) in RAW264.7 cells resulted in increased M2 polarization and decreased M1 polarization. In a rat model of SCI, grafts containing bpV(pic) reduced spinal tissue cavitation and promoted locomotor improvement, while combining grafts of bpV(pic) and acellular spinal cord (ASC) scaffolds showed a better effect. Moreover, grafts containing bpV(pic) enhanced M2 polarization and decreased M1 polarization in the macrophages during SCI. Thus, we have established that PTEN is critical for the polarization of macrophages and the functional recovery of SCI. Targeting PTEN enhances the macrophages towards to M2 polarization and promoting the functional recovery in SCI, and this suggest that PTEN may be a future therapeutic target for SCI treatment.


Assuntos
Macrófagos/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Compostos de Vanádio/farmacologia , Animais , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , PTEN Fosfo-Hidrolase/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/metabolismo , Receptores Toll-Like/metabolismo
7.
Life Sci ; 238: 116920, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610189

RESUMO

AIMS: Dendritic cells (DCs) and Toll-like receptor (TLR) participate in mediating inflammation process. However, the functional role of TLR expressed on DCs in osteoarthritis (OA) development has not been defined yet. The purpose of this study was to investigate the role and mechanism of TLR and DCs in the progression of experimental osteoarthritis (OA). MATERIALS AND METHODS: Experimental OA model was induced by iodoacetate injection. Expressions of toll-like receptors in DCs of OA mice were detected by qRT-PCR and flow cytometry. TLR agonists lipopolysaccharide (LPS) and R848 or TLR antagonist FP7 were used, and the levels of TLRs and inflammatory cytokines were examined by qRT-PCR and ELISA. KEY FINDINGS: The expression levels of TLR family members were increased in DCs derived from synovial fluid of OA mice compared with the sham mice. In vitro, OA mice-derived DCs had increased production of inflammatory cytokine after TLR agonists LPS and R848 challenge, while TLR challenges did not affect DCs maturation. Inhibition of TLR by TLR antagonist FP7 blocked TLR challenges-induced increased inflammation in DCs. In mice, administration of FP7 attenuated LPS-induced inflammatory response and OA condition. SIGNIFICANCE: Increased TLR expression in OA-derived DCs contributes to the inflammation condition and potentially acts as a therapeutic target for osteoarthritis.


Assuntos
Artrite Reumatoide/complicações , Células Dendríticas/imunologia , Inflamação/etiologia , Osteoartrite/complicações , Receptores Toll-Like/metabolismo , Animais , Citocinas/metabolismo , Células Dendríticas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL
8.
Nat Commun ; 10(1): 4115, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511519

RESUMO

TIR domain-containing adaptor inducing interferon-ß (TRIF) is an essential adaptor protein required for innate immune responses mediated by Toll-like receptor (TLR) 3- and TLR4. Here we identify USP19 as a negative regulator of TLR3/4-mediated signaling. USP19 deficiency increases the production of type I interferons (IFN) and proinflammatory cytokines induced by poly(I:C) or LPS in vitro and in vivo. Usp19-/- mice have more serious inflammation after poly(I:C) or LPS treatment, and are more susceptible to inflammatory damages and death following Salmonella typhimurium infection. Mechanistically, USP19 interacts with TRIF and catalyzes the removal of TRIF K27-linked polyubiquitin moieties, thereby impairing the recruitment of TRIF to TLR3/4. In addition, the RING E3 ubiquitin ligase complex Cullin-3-Rbx1-KCTD10 catalyzes K27-linked polyubiquitination of TRIF at K523, and deficiency of this complex inhibits TLR3/4-mediated innate immune signaling. Our findings thus reveal TRIF K27-linked polyubiquitination and deubiquitination as a critical regulatory mechanism of TLR3/4-mediated innate immune responses.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Imunidade Inata , Lisina/metabolismo , Poliubiquitina/metabolismo , Ubiquitinação , Animais , Células Cultivadas , Endopeptidases/metabolismo , Camundongos , Transdução de Sinais , Receptores Toll-Like/metabolismo
9.
Int J Mol Sci ; 20(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500298

RESUMO

TIR domain-containing proteins are essential for bacterial pathogens to subvert host defenses. This study describes a fish pathogen, Yersinia ruckeri SC09 strain, with a novel TIR domain-containing protein (STIR-2) that affects Toll-like receptor (TLR) function. STIR-2 was identified in Y. ruckeri by bioinformatics analysis. The toxic effects of this gene on fish were determined by in vivo challenge experiments in knockout mutants and complement mutants of the stir-2 gene. In vitro, STIR-2 downregulated the expression and secretion of IL-6, IL-1ß, and TNF-α. Furthermore, the results of NF-κB-dependent luciferase reporter system, co-immunoprecipitation, GST pull-down assays, and yeast two-hybrid assay indicated that STIR-2 inhibited the TLR signaling pathway by interacting with myeloid differentiation factor 88 (MyD88). In addition, STIR-2 promoted the intracellular survival of pathogenic Yersinia ruckeri SC09 strain by binding to the TIR adaptor protein MyD88 and inhibiting the pre-inflammatory signal of immune cells. These results showed that STIR-2 increased virulence in Y. ruckeri and suppressed the innate immune response by inhibiting TLR and MyD88-mediated signaling, serving as a novel strategy for innate immune evasion.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Doenças dos Peixes/microbiologia , Fator 88 de Diferenciação Mieloide/metabolismo , Yersiniose/veterinária , Yersinia ruckeri/patogenicidade , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Animais , Aderência Bacteriana , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica , Evasão da Resposta Imune , Camundongos Knockout , Oncorhynchus mykiss , Domínios Proteicos , Transdução de Sinais , Receptores Toll-Like/metabolismo , Fatores de Virulência/genética , Fatores de Virulência/imunologia , Yersiniose/imunologia , Yersinia ruckeri/genética , Yersinia ruckeri/imunologia
10.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514274

RESUMO

BACKGROUND: HIV-1 induces an uncontrolled inflammatory response of several immune components, such as inflammasomes. These molecular complexes, associated with Toll-like receptor (TLR) activity, induce the maturation and release of IL-1ß and IL-18 and eventually induce pyroptosis. It has been previously demonstrated that HIV induces inflammasome activation, which is significantly lower in the gastrointestinal tissue and blood from people living with HIV-1 with spontaneous control of viral replication. Therefore, immunomodulatory agents could be useful in improving HIV prognosis. OBJECTIVE: To evaluate the potential inhibitory effect of sulfasalazine (SSZ) on inflammasomes and TLRs in peripheral blood mononuclear cells (PBMCs) from people living with HIV and healthy donors. METHODS: PBMCs were obtained from 15 people living with HIV and 15 healthy donors. Cells were stimulated with agonists of TLRs and inflammasomes and subsequently treated with SSZ. The concentration of IL-1ß and the relative expression of NLRP3, NLRC4, NLRP1, AIM2, ASC, Caspase-1, IL-1ß, and IL-18 were quantified. RESULTS: Cells treated with SSZ exhibited a decreased IL-1ß production after inflammasome and TLR stimulation, as well as regulation of inflammasome-related genes, in both people with HIV and healthy individuals. The concentration of IL-1ß was positively correlated with the CD4+ T-cell count and negatively with the viral load. CONCLUSION: Our results suggest that SSZ has an immunomodulatory effect on inflammasome and TLR activation that depends on the clinical HIV status.


Assuntos
Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/fisiologia , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Sulfassalazina/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos T CD4-Positivos/imunologia , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfassalazina/farmacologia , Receptores Toll-Like/metabolismo , Carga Viral , Adulto Jovem
11.
Aquat Toxicol ; 215: 105286, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31479757

RESUMO

Chlorpyrifos (CPF) is an environmental pollutant with increasing importance due to its high toxicity to fish and aquatic animals. In the present study, we divided 120 common carp (Cyprinus carpio L.) into two groups including control group and CPF group, CPF group was exposed to 14.5 µg/L CPF for 30 d. 17 miRNAs were differentially expressed in CPF group head kidney tissues according to the results of miRNAome analysis. In addition, histopathological examination and electron microscopy proved that CPF exposure could lead to damage of head kidney and obvious apoptosis characteristics. The possible target genes of miRNA were predicted using online target gene prediction websites, miRNAome sequencing, GO and KEGG enrichment. miRNAome results showed that expression of miR-731 and miR-2188-3p in CPF group was 0.48 time and 0.45 time as control group, respectively. qRT-PCR results proved the reality of miRNAome. During CPF exposure, mRNA expression of TLR pathway genes and its downstream genes involved in autophagy and apoptosis pathway including TLR1, TLR2, TLR7, TLR9, MyD88, IRAK1, IRAK4, IRF7, PI3K, AKT, mTOR, Caspase3, Caspase8 and Bax were differentially increased under CPF exposure, along with ATG13 and Bcl2 decreased at the same time. Western blot results indicated that apoptosis related protein Caspase3 and Caspase8 were differentially up-regulated in the CPF group. In summary, CPF exposure could induce apoptosis while inhibited autophagy in head kidney of common carp via the regulation of miR-2188-3p and miR-731 by targeting TLR pathway. These results provide new insights for unveiling the biological effects of CPF and miRNAs in common carp.


Assuntos
Apoptose/genética , Carpas/genética , Clorpirifos/toxicidade , Rim Cefálico/lesões , MicroRNAs/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Rim Cefálico/efeitos dos fármacos , Rim Cefálico/metabolismo , Rim Cefálico/ultraestrutura , MicroRNAs/química , MicroRNAs/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade
12.
Scand J Immunol ; 90(6): e12818, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31448424

RESUMO

Bladder cancer is one of the leading causes of death worldwide. The main immune mechanisms which lead to bladder cancer development or treatment outcomes have yet to be elucidated. Toll-like receptors (TLRs) play key roles against cancer. TLRs are expressed both on immune cells and on tumour cells and drive immune responses in progression as well as treatment of cancer. Identification of signalling pathways via TLRs could revolutionize further improvement of therapeutic strategies against cancers in the future. According to the recent studies, TLRs agonists are effective immunostimulants and have important role in induction of immune responses with immunotherapeutic potential against several diseases including cancer. They play an important role in the bladder urothelium as a part of immune defence against uropathogens. On the other hand, decreased TLRs expression was found in bladder tumours, particularly in non-muscle-invasive ones. Bacillus Calmette-Guerin (BCG) (agonist of TLR2 and TLR4) is approved by US FDA for immunotherapy of bladder cancer. Despite high efficiency, immunotherapy with BCG may cause toxicity and adverse effects. Nowadays, in vitro and in vivo studies have been conducted to find alternative options for non-responder patients. Studies on TLR agonists for bladder cancer treatment have shown promising results. In this review, we discuss recent data about mechanisms played by TLRs in bladder cancer developments as well as therapeutic application of TLR agonists in cancer treatment.


Assuntos
Receptores Toll-Like/metabolismo , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/metabolismo , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Fenômenos Imunogenéticos , Imunoterapia/métodos , Ligantes , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo Genético , Transdução de Sinais , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia
13.
Fish Shellfish Immunol ; 93: 986-996, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31422176

RESUMO

Evolutionary development has increased the diversity of genotypes and the complexity of gene functions in fish. TLR22 has been identified as a teleost-specific gene, but its functions are tremendously different among different fish species. Whether the functional diversity relates to the difference of genotypes remains poorly understand. In this study, we cloned and identified three TLR22 molecules from Schizothorax prenanti (S. prenanti), named as spTLR22-1, spTLR22-2 and spTLR22-3. The full-length coding regions of spTLR22s are 2841 bp, 2805 bp and 2868 bp and coding 946 aa, 934 aa and 955 aa, respectively. All spTLR22s are composed of multiple leucine-rich repeat (LRR) domains, a transmembrane structure and a Toll/IL-1 receptor (TIR) region. The phylogenetic analysis showed that three spTLR22s were close to Cyprinus carpio TLR22-1, TLR22-2 and TLR22-3, respectively. Among the spTLR22s, they presented not close relationship but remained to belong to TLR22 subfamily. All spTLR22s were ubiquitously expressed in all tested tissues, but the expression levels of spTLR22s were dominant in immune-related tissues, such as gill and spleen. The expression levels of spTLR22-1 and spTLR22-3 were significantly increased after treatment with bacteria, LPS and Poly(I:C). However, spTLR22-2 seems like no response to these treatments. The luciferase reporter assay demonstrated that all spTLR22s could activate NF-κB signaling pathway, but only spTLR22-1 and spTLR22-2 could activate IFN-ß signaling pathway. Interestingly, in the ligand recognition analysis, spTLR22-1 and spTLR22-3 but not spTLR22-2 had the recognized potential to Poly(I:C), and all spTLR22s could not recognize LPS. Both spTLR22-1 and spTLR22-3 significantly up-regulated the expression of anti-viral-related genes (Mx, IFN and ISG15) and down-regulated the expression of anti-inflammatory factor IL-10 after the overexpression in carp EPC cell line, but spTLR22-2 failed to impact the expression of these genes. Moreover, we found that all spTLR22s localized to the intracellular region. Taken together, our results reveal that spTLR22-1 and spTLR22-3 but not spTLR22-2 may be involved into the anti-viral immune response via IFN-ß signaling pathway, and all spTLR22s can activate NF-κB signaling pathway but only spTLR22-1 and spTLR22-3 response to the stimulation of bacteria and LPS.


Assuntos
Cyprinidae/genética , Cyprinidae/imunologia , Proteínas de Peixes/genética , Expressão Gênica/imunologia , Receptores Toll-Like/genética , Animais , Fenômenos Fisiológicos Bacterianos , Linhagem Celular , Cyprinidae/metabolismo , Citocinas/metabolismo , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica/veterinária , Lipopolissacarídeos/farmacologia , Luciferases/metabolismo , Filogenia , Poli I-C/farmacologia , Análise de Sequência de Proteína/veterinária , Receptores Toll-Like/metabolismo
14.
Nat Chem Biol ; 15(9): 907-916, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31427815

RESUMO

Toll-like receptor (TLR)/myeloid differentiation primary response protein (MYD88) signaling aggravates sepsis by impairing neutrophil migration to infection sites. However, the role of intracellular fatty acids in TLR/MYD88 signaling is unclear. Here, inhibition of fatty acid synthase by C75 improved neutrophil chemotaxis and increased the survival of mice with sepsis in cecal ligation puncture and lipopolysaccharide-induced septic shock models. C75 specifically blocked TLR/MYD88 signaling in neutrophils. Treatment with GSK2194069 that targets a different domain of fatty acid synthase, did not block TLR signaling or MYD88 palmitoylation. De novo fatty acid synthesis and CD36-mediated exogenous fatty acid incorporation contributed to MYD88 palmitoylation. The binding of IRAK4 to the MYD88 intermediate domain and downstream signal activation required MYD88 palmitoylation at cysteine 113. MYD88 was palmitoylated by ZDHHC6, and ZDHHC6 knockdown decreased MYD88 palmitoylation and TLR/MYD88 activation upon lipopolysaccharide stimulus. Thus, intracellular saturated fatty acid-dependent palmitoylation of MYD88 by ZDHHC6 is a therapeutic target of sepsis.


Assuntos
Receptores Toll-Like/metabolismo , Animais , Linhagem Celular , Ácido Graxo Sintase Tipo I , Humanos , Inflamação , Lipoilação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide , NF-kappa B/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
15.
J Immunol Res ; 2019: 3575803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396542

RESUMO

Overactivation of the innate immune system together with the impaired downstream pathway of type I interferon-responding genes is a hallmark of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). To date, limited data on the cross-disease innate gene signature exists among those diseases. We compared therefore an innate gene signature of Toll-like receptors (TLRs), seven key members of the interleukin (IL)1/IL1R family, and CXCL8/IL8 in peripheral blood mononuclear cells from well-defined patients with active stages of RA (n = 36, DAS28 ≥ 3.2), SLE (n = 28, SLEDAI > 6), and SSc (n = 22, revised EUSTAR index > 2.25). Emerging diversity and abundance of the innate signature in RA patients were detected: RA was characterized by the upregulation of TLR3, TLR5, IL1RAP/IL1R3, IL18R1, and SIGIRR/IL1R8 when compared to SSc (P corr < 0.02) and of TLR2, TLR5, and SIGIRR/IL1R8 when compared to SLE (P corr < 0.02). Applying the association rule analysis, six rules (combinations and expression of genes describing disease) were identified for RA (most frequently included high TLR3 and/or IL1RAP/IL1R3) and three rules for SLE (low IL1RN and IL18R1) and SSc (low TLR5 and IL18R1). This first cross-disease study identified emerging heterogeneity in the innate signature of RA patients with many upregulated innate genes compared to that of SLE and SSc.


Assuntos
Artrite Reumatoide/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Feminino , Humanos , Imunidade Inata/genética , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Transcriptoma
16.
Parasitol Res ; 118(10): 2925-2933, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31396715

RESUMO

The effect of Toxocara canis antigens on cytokine production by human THP-1 macrophages was studied in vitro. Toxocara Excretory-Secretory products (TES) and recombinant mucins (Tc-MUC-2, Tc-MUC-3, Tc-MUC-4, and Tc-MUC-5) as well as deglycosylated forms of these antigens were used in the study. TES products stimulated macrophages to produce the innate proinflammatory IL-1ß, IL-6, and TNF-α cytokines regardless of the presence of glycans. Recombinant mucins induced glycan-dependent cytokine production. Sugar moieties led to at least 3-fold higher production of regulatory IL-10 as well as proinflammatory cytokines. The presence of glycans on mucins also affected the downstream signalling pathways in stimulated cells. The most prominent difference was noted in AKT and AMPK kinase activation. AKT phosphorylation was observed in cells stimulated with glycosylated mucins, whereas treatment with deglycosylated antigens led to AMPK phosphorylation. MAP kinase family members such as JNK and p38 and c-Jun transcription factor were phosphorylated in both cases what suggests that toll-like receptor signalling may be involved in mucin-treated macrophages. This pathway is however modified by other signalling molecules as only mucins containing intact sugars significantly induced the production of cytokines.


Assuntos
Citocinas/metabolismo , Macrófagos/imunologia , Mucinas/imunologia , Polissacarídeos/imunologia , Toxocara canis/imunologia , Animais , Linhagem Celular , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/imunologia , Células THP-1 , Receptores Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
Fish Shellfish Immunol ; 93: 395-405, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31374313

RESUMO

Radix Bupleuri extract (RBE) is one of the most popular oriental herbal medicines, which has anti-oxidative and anti-inflammatory properties. However, its protective effects and underlying molecular mechanisms on oxidative damage in tilapia are still unclear. The aims of the study were to explore the anti-oxidative, anti-inflammatory and hepatoprotective effects of RBE against oxidative damage, and to elucidate underlying molecular mechanisms in fish. Tilapia received diet containing three doses of RBE (0, 1 and 3 g/kg diet) for 60 days, and then were given an intraperitoneal injection of H2O2 or saline. Before injection, RBE treatments improved growth performance and partial anti-oxidative capacity in tilapia. After oxidative damage, RBE pretreatments were able to signally reduce the higher serum aminotransferases, alkaline phosphatase (AKP) and liver necrosis. In serum and liver, the abnormal lipid peroxidation level and antioxidant status induced by H2O2 injection were restored by RBE treatments. Furthermore, RBE treatments activated erythroid 2-related factor 2 (Nrf2) signaling pathway, which promoted the gene expression of heme oxygenase 1 (HO-1), NAD(P) H:quinone oxidoreductase 1 (NQO-1), glutathione-S-transferase (GST) and catalase (CAT). Meanwhile, RBE treatments reduced inflammatory response by inhibiting TLRs-MyD88-NF-κB signaling pathway, accompanied by the lower interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and IL-8 mRNA levels. In addition, RBE treatments upregulated complement (C3) gene expression and downregulated heat shock protein (HSP70) gene expression. In conclusion, the current study suggested that RBE pretreatments protected against H2O2-induced oxidative damage in tilapia. The beneficial activity of RBE may be due to the modulation of Nrf2/ARE and TLRs-Myd88-NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Ciclídeos/metabolismo , Proteínas de Peixes/genética , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Proteínas de Peixes/metabolismo , Fígado/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Raízes de Plantas/química , Distribuição Aleatória , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
18.
Gynecol Oncol ; 155(1): 151-160, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31375269

RESUMO

OBJECTIVE: Toll-like receptors constitute an important component of innate immune mechanism. HPV is a known etiological factor of cervical cancer and is known to interfere with the expression of TLRs and downstream signaling pathway. It remains poorly understood whether HPV modulates the expression of TLRs. Hence, understanding HPV mediated immune alterations might aid in identifying novel therapeutic targets. The aim was to study the relative gene expression of TLRs & downstream signaling pathway in cervical carcinoma. METHODS: Cervical squamous cell carcinoma (CSCC) and normal cervical tissues were obtained. Subsequent to HPV genotyping, mRNA expression profiling using PCR Array was performed. Protein expression of relevant genes with western blot was studied. Levels of cytokines in cervicovaginal washes were estimated using a Luminex multiplex platform. RESULTS: All cases of cervical cancer were HR-HPV positive and predominant subtype was HPV16 (71.1%). Significant TLR4 upregulation and TLR2,7 downregulation were observed in HR-HPV infected cervix. TLR4,7 demonstrated low expression in CSCC. Molecules from cancer allied pathways; RELA, AKT, CDKN2A, and MDM2 demonstrated upregulation in CSCC. Protein expression data corroborated with gene expression profile. A diminished level of Th1 cytokines TNF-α, IFN-É£, IL-17, and IL-12 was observed in CSCC. Significantly increased levels of IL-1ß, IL-6 and IL-2 were detected in HR-HPV infected cervix. Kaplan Meier curve demonstrated high TLR4 and low TLR7 expression was associated with poor prognosis. CONCLUSION: The study demonstrates the HPV mediated dampening of the innate immune response in CSCC and provides support for exploring potential TLR2, 7 agonists as an adjunct therapy in CSCC patients.


Assuntos
Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/fisiologia , Infecções por Papillomavirus/virologia , Receptores Toll-Like/metabolismo , Neoplasias do Colo do Útero/virologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Receptores Toll-Like/biossíntese , Receptores Toll-Like/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo
19.
Mol Immunol ; 114: 179-188, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31376731

RESUMO

The production of inflammatory cytokines is closely related to pathogen-associated molecular pattern (PAMP)-triggered activation of the Toll-like receptor (TLR), intracellular signal transduction pathways such as MAPK and NF-κB, and histone modifications. Histone methylation, a type of histone modifications, is mainly accomplished by a class of SET family proteins containing highly conserved SET domains. In the present study, we found that SET domain-containing protein 4 (SETD4) regulated inflammatory cytokines in response to TLR agonists. LPS stimulation led to the enhanced SETD4 expression, while the increased IL-6 and TNF-α release from LPS-stimulated RAW264.7 cells was attenuated by depletion of SETD4 using RNA interference. The results were further confirmed in BMDMs and pMφ isolated from SETD4-deficient mice where SETD4-/- macrophages treated with LPS, BLP or Poly(I:C) showed down-regulated IL-6 and TNF-α mRNA and protein levels when compared with SETD4+/+ macrophages. Moreover, the mRNA levels of all NF-κB-dependent genes including IL-1ß, IL-10, NFKBA, DUSP1, CCL2, CCL5, and CXCL10 in SETD4-/- macrophages were substantially reduced. To further clarify the regulatory mechanism(s) by which SETD4 modulates inflammatory cytokines, we examined the effect of SETD4 on the activation of MAPK and NF-κB signalling pathways, and found that knockout of SETD4 had no effect on phosphorylation of p38, ERK, JNK, p65, and IκBα. Notably, SETD4 translocated quickly from the cytosol to the nucleus upon LPS stimulation, suggesting that SETD4 may exert its regulatory function downstream of the MAPK and NF-κB pathways. To characterize this, we performed an in vitro HMTase assay to measure histone methyltransferase (HMTase) activity of SETD4. H3K4me1 and H3K4me2 levels were enhanced dramatically with the supplementation of SETD4, whereas both H3K4me1 and H3K4me2 were strongly attenuated in SETD4-/- BMDMs. Moreover, the LPS-stimulated recruitment of H3K4me1 and H3K4me2 at both TNF-α and IL-6 promoters was severely impaired in SETD4-/- BMDMs. Collectively, these results demonstrate that SETD4 positively regulates IL-6 and TNF-α expression in TLR agonist-stimulated macrophages by directly activating H3K4 methylation.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Citocinas/metabolismo , Lisina/metabolismo , Macrófagos/metabolismo , Metiltransferases/metabolismo , Receptores Toll-Like/metabolismo , Animais , Linhagem Celular , Histonas/metabolismo , Inflamação/metabolismo , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Fosforilação/fisiologia , Regiões Promotoras Genéticas/fisiologia , Células RAW 264.7 , Transdução de Sinais/fisiologia
20.
Life Sci ; 233: 116671, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31336122

RESUMO

Toll-like receptors (TLRs) comprise a clan of proteins involved in identification and triggering a suitable response against pathogenic attacks. As lung is steadily exposed to multiple infectious agents, antigens and host-derived danger signals, the inhabiting stromal and myeloid cells of the lung express an aggregate of TLRs which perceive the endogenously derived damage-associated molecular patterns (DAMPs) along with pathogen associated molecular patterns (PAMPs) and trigger the TLR-associated signalling events involved in host defence. Thus, they form an imperative component of host defence activation in case of microbial infections as well as non-infectious pulmonary disorders such as interstitial lung disease, acute lung injury and airways disease, such as COPD and asthma. They also play an equally important role in lung cancer. Targeting the TLR signalling network would pave ways to the design of more reliable and effective vaccines against infectious agents and control deadly infections, desensitize allergens and reduce inflammation. Moreover, TLR agonists may act as adjuvants by increasing the efficiency of cancer vaccines, thereby contributing their role in treatment of lung cancer too. Overall, TLRs present a compelling and expeditiously bolstered area of research and addressing their signalling events would be of significant use in pulmonary diseases.


Assuntos
Pneumopatias/fisiopatologia , Receptores Toll-Like/metabolismo , Animais , Humanos , Pneumopatias/imunologia , Pneumopatias/metabolismo , Transdução de Sinais
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