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1.
Autoimmun Rev ; 19(3): 102461, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917263

RESUMO

Innate immune signaling plays an important role in inflammation, and dysregulation of signaling components within this pathway has been focused as a critical mediator in initiation, progression of inflammatory autoimmune diseases. Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the immune cells, detecting pathogen associated molecular patterns, initiating signal transduction, by which interleukin-1 receptor-associated kinase (IRAK) family mediates activating signal from TLRs and interleukin-1 receptor. The family comprises of four members, IRAK1, IRAK2, IRAK-M, IRAK4. The family members have a role in either positive or negative regulation of innate immunity, adaptive immunity and inflammation. Accumulated evidence proves that IRAK performs significantly in the pathogenesis of inflammatory autoimmune disorders. On the one hand, both patients and animal modes reported abnormal expression of the family members. On the other hand, functional study in vivo and in vitro demonstrated that the members are implicated in the development of the diseases. Interestingly, IRAK inhibition has potential therapeutic benefits. In this review, we focus on the family, review the physiological roles in different immune cells, and summarize emerging data for highlighting the importance of them in inflammatory autoimmunity.


Assuntos
Doenças Autoimunes/enzimologia , Inflamação/imunologia , Quinases Associadas a Receptores de Interleucina-1/imunologia , Transdução de Sinais , Animais , Humanos , Receptores de Interleucina-1/metabolismo , Receptores Toll-Like/metabolismo
2.
Chem Biol Interact ; 315: 108897, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31726037

RESUMO

Type 2 diabetes mellitus (T2DM) is a disease with a drastically growing worldwide prevalence. It is usually associated with numerous complications of which; diabetic nephropathy (DN); is a main complication of microvasculature and more seriously, a common cause of end-stage renal disease (ESRD). Unfortunately, both the lack of a definitive remedy alongside the economic and the social burden on DN patients enforces considerable impetus for developing alternative therapies. IL-33 is a newly discovered member of the IL-1 cytokine family. IL33/ST2 signaling plays a crucial role in acute and chronic kidney diseases. Calycosin is an isoflavone with reported IL33 signaling inhibitory activity. The present study aimed to investigate if calycosin possess renal protective effect in high-fat diet/STZ-induced T2DM model and to clarify the potential underlying mechanisms. HFD-STZ control rats showed functional and structural renal damage confirmed by increased serum creatinine, blood urea nitrogen and albuminuria associated with marked renal glomerulosclerosis and interstitial fibrosis. Initiation of inflammation, oxidative stress, and fibrosis was evident as depicted by elevated renal levels of IL33/ST2 mRNA as well as increased renal NF-κBp65, TNF-α, IL-1ß, MDA, and TGF-ß contents with suppressed Nrf2 and TAC. Calycosin treatment markedly improved the aforementioned makers of renal injury and dysfunction, modulated IL33/ST2 signaling, inflammatory cytokines, oxidative stress and fibrotic processes. This was accompanied by improvement of T2DM-induced renal ultramicroscopic and histopathological alterations.


Assuntos
Fibrose/tratamento farmacológico , Interleucina-33/metabolismo , Isoflavonas/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores de Interleucina-1/metabolismo , Animais , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fibrose/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-31866568

RESUMO

Interleukin-1ß (IL-1ß) is a pivotal proinflammatory cytokine that plays important roles in regulating immune responses and in inducing a series of inflammatory reactions in response to infection. Recently, increasing attention has focused on the regulatory mechanisms of IL-1ß activity in teleosts. In this regard, IL-1 receptor type 1 plays a crucial role in immune responses, whereas IL-1 receptor type 2 is a decoy receptor that functions as an IL-1ß signaling inhibitor. However, the interactions of these three proteins with respect to fish immunity have rarely been studied. In the present study, cDNAs of the il1b, il1r1, and il1r2 genes of the barbel steed (Hemibarbus labeo) were cloned and sequenced. Amino acid sequence analysis revealed that the IL-1ß protein and its two receptors identified in barbel steed are conserved in most teleosts, whereas phylogenetic tree analysis indicated that these three proteins are closely related to those of cyprinids. In response to lipopolysaccharide treatment, expression of the genes encoding IL-1ß and its two receptors was significantly upregulated in the immune-related tissues of barbel steed. Furthermore, expression of the il1r1 and il1r2 genes was induced in monocytes/macrophages in response to stimulation with recombinant IL-1ß.


Assuntos
Cyprinidae/metabolismo , Proteínas de Peixes/metabolismo , Interleucina-1beta/metabolismo , Receptores de Interleucina-1/metabolismo , Sequência de Aminoácidos , Animais , Células Cultivadas , Cyprinidae/genética , Proteínas de Peixes/genética , Perfilação da Expressão Gênica , Interleucina-1beta/genética , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Filogenia , Receptores de Interleucina-1/genética , Homologia de Sequência
4.
Nat Commun ; 10(1): 4003, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488830

RESUMO

Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis.


Assuntos
Citocinas/metabolismo , Microbioma Gastrointestinal/fisiologia , Interleucina-1/metabolismo , Doenças Metabólicas/metabolismo , Obesidade/metabolismo , Animais , Colo/imunologia , Colo/microbiologia , Colo/patologia , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal/imunologia , Expressão Gênica , Teste de Tolerância a Glucose , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucina-2/metabolismo , Obesidade/imunologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transcriptoma , Verrucomicrobia
5.
Nat Rev Neurol ; 15(8): 459-472, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263255

RESUMO

Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor-Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress and transforming growth factor-ß signalling associated with blood-brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities.


Assuntos
Encefalite/diagnóstico , Encefalite/metabolismo , Epilepsia/diagnóstico , Epilepsia/terapia , Animais , Ácido Araquidônico/metabolismo , Biomarcadores/sangue , Encefalite/complicações , Epilepsia/complicações , Epilepsia/metabolismo , Humanos , Estresse Oxidativo , Prostaglandinas/metabolismo , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/metabolismo
6.
Cells ; 8(6)2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207932

RESUMO

Phycocyanin is a type of marine functional food additive, exerting a health care efficacy with no side effects. It has been shown that phycocyanin possesses anticancer function in non-small cell lung cancer (NSCLC) cells, but the underlying regulatory mechanism still remains unclear. Further investigation on the antineoplastic mechanism of phycocyanin would provide useful information on NSCLC treatment. In this study, we explored the in vitro function and mechanism of phycocyanin in three typical NSCLC cell lines, H1975, H1650, and LTEP-a2, for the first time. Phenotypic experiments showed that phycocyanin significantly induced the apoptosis as well as suppressed the growth of NSCLC cells. Transcriptome analysis suggested that toll/interleukin 1 receptor domain-containing adaptor protein (TIRAP) was significantly down-regulated by phycocyanin. Strikingly, similar to phycocyanin-treated assays, siRNA knockdown of TIRAP expression also resulted in the anti-proliferative phenomenon in NSCLC cells. In addition, the activity of NF-κB signaling was also suppressed after silencing TIRAP expression, revealing that phycocyanin exerted anti-proliferative function through down-regulating TIRAP/NF-κB activity in NSCLC cells. Collectively, this study has laid a theoretical basis on the treatment of NSCLC and the potential utilization of marine functional products.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação para Baixo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Ficocianina/uso terapêutico , Receptores de Interleucina-1/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Ficocianina/farmacologia , Transcriptoma/genética
7.
MAbs ; 11(5): 956-964, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31068073

RESUMO

Accurate prediction of the human pharmacokinetics (PK) of a candidate monoclonal antibody from nonclinical data is critical to maximize the success of clinical trials. However, for monoclonal antibodies exhibiting nonlinear clearance due to target-mediated drug disposition, PK predictions are particularly challenging. That challenge is further compounded for molecules lacking cross-reactivity in a nonhuman primate, in which case a surrogate antibody selective for the target in rodent may be required. For these cases, prediction of human PK must account for any interspecies differences in binding kinetics, target expression, target turnover, and potentially epitope. We present here a model-based method for predicting the human PK of MAB92 (also known as BI 655130), a humanized IgG1 κ monoclonal antibody directed against human IL-36R. Preclinical PK was generated in the mouse with a chimeric rat anti-mouse IgG2a surrogate antibody cross-reactive against mouse IL-36R. Target-specific parameters such as antibody binding affinity (KD), internalization rate of the drug target complex (kint), target degradation rate (kdeg), and target abundance (R0) were integrated into the model. Two different methods of assigning human R0 were evaluated: the first assumed comparable expression between human and mouse and the second used high-resolution mRNA transcriptome data (FANTOM5) as a surrogate for expression. Utilizing the mouse R0 to predict human PK, AUC0-∞ was substantially underpredicted for nonsaturating doses; however, after correcting for differences in RNA transcriptome between species, AUC0-∞ was predicted largely within 1.5-fold of observations in first-in-human studies, demonstrating the validity of the modeling approach. Our results suggest that semi-mechanistic models incorporating RNA transcriptome data and target-specific parameters may improve the predictivity of first-in-human PK.


Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Receptores de Interleucina-1/imunologia , Animais , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Ratos , Receptores de Interleucina-1/metabolismo , Estudos Retrospectivos , Transcriptoma
8.
Dev Comp Immunol ; 99: 103401, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31145914

RESUMO

The interleukin (IL) -1 family members play an important role in regulating inflammatory responses and their functions are mediated by a group of receptors consisting of immunoglobulin and Toll/IL-1 receptor (TIR) domains. In humans, 10 IL-1Rs are found. In this study, 5 IL-1 receptors including IL-1R3/IL-1RAcP, IL-1R8/SIGIRR, IL-1R9a/IL-1RAcPL1a, IL-1R9b/IL-1RAcPL1b and IL-1R10/IL-1RAcPL2 were identified in grass carp (Ctenopharyngodon idella). Phylogenetic analysis reveals that the IL-1R9a/IL-1RAcPL1a and IL-1R9b/IL-1RAcPL1b share significantly high sequence similarity and are believed to have been duplicated from the same gene prior to the radiation of teleosts. Further, these two receptors closely relate to the IL-1R10/IL-1RAcPL2, suggesting that they may have evolved from a common ancestor. The IL-1R3/IL-1RAcP, IL-1R9a/IL-1RAcPL1a, IL-1R9b/IL-1RAcPL1b and IL-1R10/IL-1RAcPL2 are highly expressed in the brain. Stimulation of primary spleen leucocytes by LPS and intraperitoneal injection of fish with poly (I:C) or bacterial infection results in significant increases of IL-1R3/IL-1RAcP expression. Interestingly, the IL-1R8/SIGIRR and IL-1R10/IL-1RAcPL2 showed similar expression patterns.


Assuntos
Carpas/classificação , Carpas/imunologia , Proteínas de Peixes/genética , Regulação da Expressão Gênica/imunologia , Filogenia , Receptores de Interleucina-1/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Carpas/genética , Células Cultivadas , Evolução Molecular , Proteínas de Peixes/química , Proteínas de Peixes/imunologia , Duplicação Gênica , Expressão Gênica , Imunidade Inata/genética , Receptores de Interleucina-1/química , Receptores de Interleucina-1/metabolismo , Alinhamento de Sequência , Distribuição Tecidual
9.
Vet Microbiol ; 232: 128-136, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31030836

RESUMO

The interleukin-1 (IL-1) family of cytokines, particularly IL-1α and IL-1ß, are potent regulators of innate immunity that play key roles in host defense against infection, hence we evaluated the role of these cytokines in the control of brucellosis within RAW 264.7 cells. Marked expression and secretion of IL-1α and IL-1ß were observed during Brucella infection in macrophages. Blocking of IL-1α and IL-1ß reduced induction of IL-10, IL-1ß and TNF, and IL-6 and TNF, respectively. However, interference of IL-1α and not IL-1ß signaling notably augmented susceptibility of macrophages to Brucella infection which indicates that IL-1α is required for a downstream signaling cascade of innate immunity for efficient clearance of Brucella. This protection requires binding to interleukin-1 receptor (IL-1R) mediated by myeloid differentiation factor 88 (MyD88) signaling and associated with increased lysosomal-mediated killing and nitric oxide (NO) production. Expression of pro-inflammatory cytokines was observed to be mediated via NF-κB-p50, HIF-1α and CEBPA, but negatively controlled by CEBPB while transcription of some important phagolysosomal genes was regulated via CEBPA and c-Jun which indicates the important role of these transcription factors in the control of Brucella infection in macrophages via IL-1α signaling pathway.


Assuntos
Brucella abortus/patogenicidade , Interleucina-1alfa/imunologia , Macrófagos/imunologia , Óxido Nítrico/imunologia , Animais , Imunidade Inata , Interleucina-1alfa/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Macrófagos/microbiologia , Camundongos , Viabilidade Microbiana , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Células RAW 264.7 , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
10.
Mol Biol Rep ; 46(2): 2493-2504, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30919211

RESUMO

Osteoarthritis (OA) is a degenerative joint disease, in which low-grade inflammation plays an important role at the initiating step. Low-doses of LPS-induced inflammation in the plasma activate chondrocytes and promote the secretion proinflammatory cytokines, leading to secondary inflammation. Blocking OA-associated TLR activation is a promising strategy for the development of suitable therapies. Here, we want to find some bacteria-derived peptides that can block TLR signaling in chondrocytes more efficiently. Based on previous studies, we screened 12 TIR domain-derived peptides for their effects on NF-кB activation induced by LPS, IL-1ß or TNF-α in murine ATDC-5 cells. We evaluated their effects on LPS-induced cytokine expression and secretion. Among them, two bacteria-derived peptides, TcpC-DD and TcpB-DD, showed the most potent inhibitory activities. In comparison with TcpB-DD, TcpC-DD exhibited broader TLR-inhibitory specificity during inflammation in chondrocytes. Furthermore, both TcpC-DD and TcpB-DD displayed strong inhibition of LPS- and IL-1ß-induced catabolic reactions in chondrocytes. However, only TcpC-DD exhibited obvious suppression of TNF-α-induced catabolism. In conclusion, we identified two novel inhibitory peptides that modulate catabolism in chondrocytes and innate immune responses, and these peptides could be used to develop novel therapeutic strategies for OA.


Assuntos
Proteínas da Membrana Bacteriana Externa/farmacologia , Condrócitos/imunologia , Imunidade Inata/efeitos dos fármacos , Animais , Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismo , Linhagem Celular , Células Cultivadas , Citocinas/metabolismo , Humanos , Imunidade Inata/imunologia , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Camundongos , NF-kappa B/metabolismo , Osteoartrite/imunologia , Osteoartrite/fisiopatologia , Peptídeos/metabolismo , Domínios Proteicos , Receptores de Interleucina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
11.
Expert Opin Ther Pat ; 29(4): 243-259, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30916602

RESUMO

INTRODUCTION: Interleukin-1 receptor-associated kinase 4 (IRAK4) is the most upstream kinase in Toll/Interleukin-1 receptor (TIR) signaling. Human and rodent genetics support the role of IRAK4 in immune function and the involvement of IRAK4-dependent signaling in certain cancers is hypothesized. The accumulating evidence has motivated the discovery of IRAK4 inhibitors that could be used therapeutically. AREAS COVERED: This review summarizes patents published in 2016-2018 claiming IRAK4 inhibitors. Representative analogues from each patent are presented with a focus on compounds that have been profiled in cellular and in vivo assays. EXPERT OPINION: The last three years have seen an increased number of IRAK4 inhibitors with which to assess the therapeutic potential of the target. At least 5 companies are believed to have advanced to the clinic. Pfizer is in phase II for rheumatoid arthritis (RA). The outcomes of these studies should inform on the therapeutic potential in autoimmune disease and cancer.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Artrite Reumatoide/enzimologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/enzimologia , Desenvolvimento de Medicamentos/métodos , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Patentes como Assunto , Receptores de Interleucina-1/metabolismo
12.
Int Immunopharmacol ; 71: 188-197, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909134

RESUMO

Bacterial endotoxin-induced sepsis causes 30-40% of the deaths in the intensive care unit (ICU) globally, for which there is no pharmacotherapy. Lipopolysaccharide (LPS), a bacterial endotoxin, stimulates the Toll-like receptor (TLR)-4 signalling pathways to upregulate the expression of various inflammatory mediators. Here, we show that the TIRAP and c-Jun protein signalling complex forms in macrophages in response to LPS stimulation, which increases the AP1 transcriptional activity, thereby amplifying the expression of inflammatory mediators. Using a computer-aided molecular docking platform, we identified gefitinib as a putative inhibitor of the TIRAP-c-Jun signalling complex. Further, we demonstrated the ability of gefitinib to inhibit the interaction of TIRAP-c-Jun with in vitro experiments and with a mouse model of sepsis. Importantly, pre-treatment with gefitinib increased the survival of the mice that received a lethal dose of LPS compared to that of the controls. These findings verify the ability of gefitinib to directly disrupt the interaction of TIRAP and c-Jun, thereby inhibiting a major inflammatory response that is often observed in patients experiencing sepsis.


Assuntos
Gefitinibe/farmacologia , Macrófagos/fisiologia , Glicoproteínas de Membrana/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-jun/antagonistas & inibidores , Receptores de Interleucina-1/antagonistas & inibidores , Sepse/tratamento farmacológico , Animais , Células Cultivadas , Modelos Animais de Doenças , Gefitinibe/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-jun/metabolismo , Receptores de Interleucina-1/metabolismo , Sepse/imunologia , Sepse/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo
13.
Neurochem Res ; 44(5): 1214-1227, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30859436

RESUMO

Neuropathic pain (NP) has complicated pathogenesis as it mainly involves a lesion or dysfunction of the somatosensory nervous system and its clinical treatment remains challenging. Chronic constriction injury (CCI) model is a widely used neuropathic pain model and involved in mechanisms including both nerve inflammatory and injury. Cytokines and their receptors play essential roles in the occurrence and persistence of neuropathic pain, but the underlying mechanisms have not well been understood. Therefore, Interleukin-1 receptor-associated kinase 1 (IRAK1) is chosen to explore the possible mechanisms of NP. In the present study, IRAK1 was found to persistently increase in the dorsal root ganglion (DRG) and spinal cord (SC) during CCI detected by western blot. The staining further confirmed that IRAK1 was mainly co-located in the DRG astrocytes or SC neurons, but less in the DRG microglia or SC astrocytes. Moreover, the region of increased IRAK1 expression was observed in superficial laminae of the spinal dorsal horn, which was the nociceptive neuronal expression domain, suggesting that IRAK1 may mediated CCI-induced pain by nociceptive primary afferent. In addition, intrathecal injection of Toll-like receptor 4 (TLR4) inhibitor or IRAK1 siRNA decreased the expression of IRAK1 accompanied with the alleviation of CCI-induced neuropathic pain. The upregulation of p-NF-κB expression was reversed by IRAK1 siRNA in SC, and intrathecal injection of p-NF-κB inhibitor relieved neuropathic pain. Taking together, targeting IRAK1 may be a potential treatment for chronic neuropathic pain.


Assuntos
Gânglios Espinais/metabolismo , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Nervo Isquiático/lesões , Animais , Doença Crônica , Constrição , Gânglios Espinais/lesões , Hiperalgesia/metabolismo , Masculino , Microglia/metabolismo , Nociceptores/metabolismo , Ratos Sprague-Dawley , Receptores de Interleucina-1/metabolismo , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
14.
Nat Commun ; 10(1): 709, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755603

RESUMO

T cells generate antigen-specific immune responses to their cognate antigen as a hallmark of adaptive immunity. Despite the importance of antigen-specific T cells, here we show that antigen non-related, bystander memory-like CD4+ T cells also significantly contribute to autoimmune pathogenesis. Transcriptome analysis demonstrates that interleukin (IL)-1ß- and IL-23-prime T cells that express pathogenic TΗ17 signature genes such as RORγt, CCR6, and granulocyte macrophage colony-stimulating factor (GM-CSF). Importantly, when co-transferred with myelin-specific 2D2 TCR-transgenic naive T cells, unrelated OT-II TCR-transgenic memory-like TH17 cells infiltrate the spinal cord and produce IL-17A, interferon (IFN)-γ, and GM-CSF, increasing the susceptibility of the recipients to experimental autoimmune encephalomyelitis in an IL-1 receptor-dependent manner. In humans, IL-1R1high memory CD4+ T cells are major producers of IL-17A and IFN-γ in response to IL-1ß and IL-23. Collectively, our findings reveal the innate-like pathogenic function of antigen non-related memory CD4+ T cells, which contributes to the development of autoimmune diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Imunidade Adaptativa , Animais , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Interferon gama/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptores CCR6/genética , Receptores de Interleucina-1/metabolismo , Medula Espinal/imunologia , Medula Espinal/patologia , Células Th17/imunologia , Células Th17/metabolismo
15.
J Biol Chem ; 294(12): 4596-4607, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30647133

RESUMO

Pregnenolone is a steroid hormone precursor that is synthesized in various steroidogenic tissues, in the brain, and in lymphocytes. In addition to serving as the precursor for other steroid hormones, pregnenolone exerts its own effect as an anti-inflammatory molecule to maintain immune homeostasis in various inflammatory conditions. Pregnenolone and its metabolic derivatives have been shown to have beneficial effects in the brain, including enhancing memory and learning, reversing depressive disorders, and modulating cognitive functions. A decreased level of pregnenolone has been observed in neuroinflammatory diseases, which emphasizes its role in neuroprotection and neuroregeneration. Although the anti-inflammatory property of pregnenolone was recognized several decades ago, its mechanism of action remains unknown. Here we report that pregnenolone promotes ubiquitination and degradation of the TLR2/4 adaptor protein TIRAP and TLR2 in macrophages and microglial cells. Pregnenolone and its metabolites suppressed the secretion of tumor necrosis factor α and interleukin-6 mediated through TLR2 and TLR4 signaling. Pregnenolone has been reported to induce activation of cytoplasmic linker protein 170, and this protein has recently been shown to promote targeted degradation of TIRAP. We observed enhanced degradation of TIRAP and TLR4 suppression by cytoplasmic linker protein 170 in the presence of pregnenolone. Our experimental data reveal novel nongenomic targets of pregnenolone and provide important leads to understand its role in restoring immune homeostasis in various inflammatory conditions.


Assuntos
Imunidade Inata , Inflamação/metabolismo , Glicoproteínas de Membrana/metabolismo , Pregnenolona/metabolismo , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Células HEK293 , Humanos , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteólise , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação
16.
Gastroenterology ; 156(4): 1082-1097.e11, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30452921

RESUMO

BACKGROUND & AIMS: Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) that frequently results in functional damage, bowel obstruction, and surgery. Interleukin (IL) 36 is a group of cytokines in the IL1 family with inflammatory effects. We studied the expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in the development of intestinal fibrosis in human tissues and mice. METHODS: We obtained intestinal tissues from 92 patients with Crohn's disease (CD), 48 patients with ulcerative colitis, and 26 patients without inflammatory bowel diseases (control individuals). Tissues were analyzed by histology to detect fibrosis and by immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome-wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R, and we studied intestinal tissues from Il1rl2-/- mice; colitis and fibrosis were induced in mice by repetitive administration of DSS or TNBS. Bone marrow cells were transplanted from Il1rl2-/- to irradiated wild-type mice and intestinal tissues were analyzed. Antibodies against IL36R were applied to mice with established chronic colitis and fibrosis and intestinal tissues were studied. RESULTS: Mucosal and submucosal tissue from patients with CD or ulcerative colitis had higher levels of collagens, including type VI collagen, compared with tissue from control individuals. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed α-smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2-/- mice and mice given injections of an antibody against IL36R developed less severe colitis and fibrosis after administration of DSS or TNBS, but bone marrow cells from Il1rl2-/- mice did not prevent induction of colitis and fibrosis. Injection of antibodies against IL36R significantly reduced established fibrosis in mice with chronic intestinal inflammation. CONCLUSION: We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD compared with control individuals. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R gene in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD.


Assuntos
Colite Ulcerativa/metabolismo , Colágeno Tipo VI/metabolismo , Colo/patologia , Doença de Crohn/metabolismo , Interleucina-1/metabolismo , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Receptores de Interleucina-1/metabolismo , Actinas/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Estudos de Casos e Controles , Células Cultivadas , Colite/induzido quimicamente , Colite/patologia , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Sulfato de Dextrana , Fibroblastos/efeitos dos fármacos , Fibrose , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Interleucina-1/farmacologia , Ligantes , Camundongos , Camundongos Knockout , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/genética , Transdução de Sinais , Transcriptoma , Ácido Trinitrobenzenossulfônico
17.
Brain Behav Immun ; 76: 126-138, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30453020

RESUMO

The cytokine interleukin-1 (IL-1) is a key contributor to neuroinflammation and brain injury, yet mechanisms by which IL-1 triggers neuronal injury remain unknown. Here we induced conditional deletion of IL-1R1 in brain endothelial cells, neurons and blood cells to assess site-specific IL-1 actions in a model of cerebral ischaemia in mice. Tamoxifen treatment of IL-1R1 floxed (fl/fl) mice crossed with mice expressing tamoxifen-inducible Cre-recombinase under the Slco1c1 promoter resulted in brain endothelium-specific deletion of IL-1R1 and a significant decrease in infarct size (29%), blood-brain barrier (BBB) breakdown (53%) and neurological deficit (40%) compared to vehicle-treated or control (IL-1R1fl/fl) mice. Absence of brain endothelial IL-1 signalling improved cerebral blood flow, followed by reduced neutrophil infiltration and vascular activation 24 h after brain injury. Conditional IL-1R1 deletion in neurons using tamoxifen inducible nestin-Cre mice resulted in reduced neuronal injury (25%) and altered microglia-neuron interactions, without affecting cerebral perfusion or vascular activation. Deletion of IL-1R1 specifically in cholinergic neurons reduced infarct size, brain oedema and improved functional outcome. Ubiquitous deletion of IL-1R1 had no effect on brain injury, suggesting beneficial compensatory mechanisms on other cells against the detrimental effects of IL-1 on endothelial cells and neurons. We also show that IL-1R1 signalling deletion in platelets or myeloid cells does not contribute to brain injury after experimental stroke. Thus, brain endothelial and neuronal (cholinergic) IL-1R1 mediate detrimental actions of IL-1 in the brain in ischaemic stroke. Cell-specific targeting of IL-1R1 in the brain could therefore have therapeutic benefits in stroke and other cerebrovascular diseases.


Assuntos
Isquemia Encefálica/imunologia , Interleucina-1/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Citocinas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Inflamação/metabolismo , Interleucina-1/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Receptores de Interleucina-1/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de Sinais
18.
Immunobiology ; 224(1): 50-59, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429052

RESUMO

The Gram-negative bacterium Porphyromonas gingivalis is strongly associated with periodontitis. We previously demonstrated that P2X7 receptor activation by extracellular ATP (eATP) triggers elimination of intracellular pathogens, such as Leishmania amazonensis, Toxoplasma gondii and Chlamydia trachomatis. We also showed that eATP-induced IL-1ß secretion via the P2X7 receptor is impaired by P. gingivalis fimbriae. Furthermore, enhanced P2X7 receptor expression was detected in the maxilla of P. gingivalis-orally infected mice as well as in human periodontitis patients. Here, we examined the effect of P2X7-, caspase-1/11- and IL-1 receptor-mediated responses during P. gingivalis infection. P2X7 receptor played a large role in controlling P. gingivalis infection and P. gingivalis-induced recruitment of inflammatory cells, especially neutrophils. In addition, IL-1ß secretion was detected at different time points only when P2X7 receptor was expressed and in the presence of eATP treatment ex vivo. Activation of P2X7 receptor and IL-1 receptor by eATP and IL-1ß, respectively, promoted P. gingivalis elimination in macrophages. Interestingly, eATP-induced P. gingivalis killing was inhibited by the IL-1 receptor antagonist (IL-1RA), consistent with autocrine activation of the IL-1 receptor for P. gingivalis elimination. In vivo, caspase-1/11 and IL-1 receptor were also required for bacterial clearance, leukocyte recruitment and IL-1ß production after P. gingivalis infection. Our data demonstrate that the P2X7-IL-1 receptor axis activation is required for effective innate immune responses against P. gingivalis infection.


Assuntos
Infecções por Bacteroidaceae/imunologia , Leucócitos/imunologia , Macrófagos/imunologia , Porphyromonas gingivalis/fisiologia , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Comunicação Autócrina , Caspase 1/genética , Caspase 1/metabolismo , Caspases/genética , Caspases/metabolismo , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Receptores Purinérgicos P2X7/genética , Transdução de Sinais
19.
Int J Hyperthermia ; 36(1): 151-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30484725

RESUMO

Hyperthermia in pigs induces suppressor of cytokine signaling (SOCS) 3 and SOCS4 expression in intestinal gut and causes disruption of inflammation cytokine production. These changes may affect the development of inflammatory bowel disease in heat-stressed pigs. However, the mechanisms are not well understood. Accordingly, in this study, we examined the roles of SOCS members in regulation of the nuclear factor (NF)-κB pathway and heat shock protein (HSP) 70-mediated cytokine induction in 293T human embryonic kidney cells and IPEC-J2 porcine small intestinal epithelial cells. Ectopic expression of HSP70 significantly modulated NF-κB activity (p ≤ .05). Moreover, co-expression of SOCS3 or SOCS4 with HSP70 reduced NF-κB activity, which was abolished by SOCS3 or SOCS4 knockdown with short hairpin RNA. Interestingly, MyD88-adaptor-like (Mal) protein was downregulated in cells expressing SOCS3 but not in cells expressing SOCS4. In addition, SOCS3 but not SOCS4 negatively regulated the activity of NF-κB induced by HSP70 overexpression via degradation of Mal. These findings may facilitate the development of novel SOCS3-based therapeutic strategies to control heat stress-related disorders in pigs.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Glicoproteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Receptores de Interleucina-1/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Animais , Linhagem Celular , Células HEK293 , Humanos , Proteína 3 Supressora da Sinalização de Citocinas/genética , Suínos , Transfecção
20.
Brain Behav Immun ; 76: 37-47, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30394314

RESUMO

Toll-like receptor-4 (TLR4) is a transmembrane receptor that initiates an immune response following a bacterial infection or host derived molecules associated with cellular distress. Beyond triggering inflammation, TLR4 has been implicated in modulating behavioral and cognitive processes in a physiologically normal state, as young adult TLR4 deficient mice show learning enhancements in select tasks. Currently unknown is whether these benefits are present in both sexes and persist with aging. The present study evaluated spatial memory, anxiety-like behavior, and central levels of pro- and anti-inflammatory molecules in young (4-5 months) and aged (18-19 months) TLR4 deficient (TLR4-/-) and wild-type (WT) male and female mice. Results confirmed that TLR4-/- mice show enhanced spatial memory compared to WT mice. These effects were age- and sex-specific, as memory retention was superior in the TLR4-/- young males and aged females. While TLR4-/- mice showed age-related changes in behavior, these changes were attenuated relative to aged WT mice. Further, aged TLR4-/- mice showed differential expression of molecules involved in interleukin (IL)-1 signaling in the hippocampus. For instance, aged TLR4-/- females showed heightened expression of IL-1 receptor antagonist (IL-1ra) and the IL-1 accessory proteins AcP and AcPb. Collectively, these data provide the initial evidence that TLR4 deficiency enhances cognitive function and modulates the inflammatory profile of the hippocampus in a sex- and age-dependent manner.


Assuntos
Interleucina-1/genética , Memória Espacial/fisiologia , Receptor 4 Toll-Like/metabolismo , Fatores Etários , Animais , Ansiedade/genética , Ansiedade/metabolismo , Cognição/fisiologia , Feminino , Hipocampo/metabolismo , Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1/metabolismo , Lipopolissacarídeos/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-1/metabolismo , Fatores Sexuais , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/genética
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