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1.
PLoS Pathog ; 16(9): e1008811, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32903274

RESUMO

Damage-associated molecular patterns (DAMPs) are endogenous molecules activating the immune system upon release from injured cells. Here we show that the IFI16 protein, once freely released in the extracellular milieu of chronically inflamed tissues, can function as a DAMP either alone or upon binding to lipopolysaccharide (LPS). Specifically, using pull-down and saturation binding experiments, we show that IFI16 binds with high affinity to the lipid A moiety of LPS. Remarkably, IFI16 DAMP activity is potentiated upon binding to subtoxic concentrations of strong TLR4-activating LPS variants, as judged by TLR4-MD2/TIRAP/MyD88-dependent IL-6, IL-8 and TNF-α transcriptional activation and release in stimulated monocytes and renal cells. Consistently, using co-immunoprecipitation (co-IP) and surface plasmon resonance (SPR) approaches, we show that IFI16 is a specific TLR4-ligand and that IFI16/LPS complexes display a faster stimulation turnover on TLR4 than LPS alone. Altogether, our findings point to a novel pathomechanism of inflammation involving the formation of multiple complexes between extracellular IFI16 and subtoxic doses of LPS variants, which then signal through TLR4.


Assuntos
Inflamação/imunologia , Neoplasias Renais/imunologia , Leucemia/imunologia , Lipopolissacarídeos/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Receptor 4 Toll-Like/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Leucemia/metabolismo , Leucemia/patologia , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas
2.
PLoS One ; 15(8): e0237034, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745117

RESUMO

Production of IFN-γ is a key innate immune mechanism that limits replication of intracellular bacteria such as Francisella tularensis (Ft) until adaptive immune responses develop. Previously, we demonstrated that the host cell types responsible for IFN-γ production in response to murine Francisella infection include not only natural killer (NK) and T cells, but also a variety of myeloid cells. However, production of IFN-γ by mouse dendritic cells (DC) is controversial. Here, we directly demonstrated substantial production of IFN-γ by DC, as well as hybrid NK-DC, from LVS-infected wild type C57BL/6 or Rag1 knockout mice. We demonstrated that the numbers of conventional DC producing IFN-γ increased progressively over the course of 8 days of LVS infection. In contrast, the numbers of conventional NK cells producing IFN-γ, which represented about 40% of non-B/T IFN-γ-producing cells, peaked at day 4 after LVS infection and declined thereafter. This pattern was similar to that of hybrid NK-DC. To further confirm IFN-γ production by infected cells, DC and neutrophils were sorted from naïve and LVS-infected mice and analyzed for gene expression. Quantification of LVS by PCR revealed the presence of Ft DNA not only in macrophages, but also in highly purified, IFN-γ producing DC and neutrophils. Finally, production of IFN-γ by infected DC was confirmed by immunohistochemistry and confocal microscopy. Notably, IFN-γ production patterns similar to those in wild type mice were observed in cells derived from LVS-infected TLR2, TLR4, and TLR2xTLR9 knockout (KO) mice, but not from MyD88 KO mice. Taken together, these studies demonstrate the pivotal roles of DC and MyD88 in IFN-γ production and in initiating innate immune responses to this intracellular bacterium.


Assuntos
Interferon gama/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Receptores Toll-Like/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Francisella tularensis/imunologia , Imunidade Inata/imunologia , Células Matadoras Naturais/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Neutrófilos/metabolismo , Baço/metabolismo , Linfócitos T/imunologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/imunologia , Tularemia/microbiologia
3.
Cancer Sci ; 111(9): 3327-3337, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32639651

RESUMO

Tirabrutinib is a second-generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment-naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström's macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression-free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow-up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug-related atrial fibrillation or hypertension. Although the follow-up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI-173646).


Assuntos
Imidazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Genótipo , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Gradação de Tumores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/etiologia
4.
J Toxicol Sci ; 45(7): 401-409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612008

RESUMO

Dihydropyrazines (DHPs), including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are glycation products that are spontaneously generated in vivo and ingested via food. DHPs generate various radicals and reactive oxygen species (ROS), which can induce the expression of several antioxidant genes in HepG2 cells. However, detailed information on DHP-response pathways remains elusive. To address this issue, we investigated the effects of DHP-3 on the nuclear factor-κB (NF-κB) pathway, a ROS-sensitive signaling pathway. In lipopolysaccharide-stimulated (LPS-stimulated) HepG2 cells, DHP-3 decreased phosphorylation levels of inhibitor of NF-κB (IκB) and NF-κB p65, and nuclear translocation of NF-κB p65. In addition, DHP-3 reduced the expression of Toll-like receptor 4 (TLR4) and the adaptor protein myeloid differentiation primary response gene 88 (MyD88). Moreover, DHP-3 suppressed the mRNA expression of tumor necrosis factor-alpha (TNFα), and interleukin-1 beta (IL-1ß). Taken together, these results suggest that DHP-3 acts as a negative regulator of the TLR4-MyD88-mediated NF-κB signaling pathway.


Assuntos
Dicarbetoxi-Di-Hidrocolidina/análogos & derivados , Lipopolissacarídeos/efeitos adversos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Dicarbetoxi-Di-Hidrocolidina/efeitos adversos , Dicarbetoxi-Di-Hidrocolidina/toxicidade , Produtos Finais de Glicação Avançada , Células Hep G2 , Humanos , Interleucina-1beta/metabolismo , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
PLoS One ; 15(6): e0233643, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479555

RESUMO

Chronic subdural hematoma (CSDH) is an angiogenic and inflammatory disease. Toll-like receptors (TLRs) transduce intracellular signals, resulting in the activation of nuclear factor κB (NF-κB), which leads to the production of inflammatory cytokines. High-mobility group box 1 (HMGB1) functions as a mediator of inflammatory responses through TLRs. In this study, we examined the expression of HMGB1 and components of the Toll-like receptor and NF-κB signaling pathways in the outer membrane of CSDH. Eight patients whose outer membrane was successfully obtained during trepanation surgery were included in this study. The expression of TLR4, myeloid differentiation factor 88 (MyD88), interleukin-1 receptor-associated kinase 4 (IRAK4), TNF receptor-associated factor 6 (TRAF6), TGFß-activated kinase 1 (Tak1), interferon regulatory factors 3 (IRF3), IκB kinase ß (IKKß), IKKγ, IκBε, IκBα, NF-κB/p65 and ß-actin was examined by Western blot analysis. The expression of TLR4, NF-κB/p65 and interleukin-6 (IL-6) was also examined by immunohistochemistry. The concentrations of HMGB1 and IL-6 in CSDH fluids were measured using ELISA kits. Above-mentioned molecules were detected in all cases. In addition, TLR4, NF-κB/p65 and IL-6 were localized in the endothelial cells of vessels within CSDH outer membranes. The concentrations of HMGB1 and IL-6 in CSDH fluids were significantly higher than that in the CSF and serum. There existed a correlation between the concentrations of HMGB1 and IL-6 in CSDH fluids. Our data suggest that HMGB1 in CSDH fluids produces the inflammatory cytokine IL-6 in endothelial cells through the Toll-like receptor and NF-κB signaling pathways. Anti-HMGB1 therapy might be a useful method to treat the growth of CSDH.


Assuntos
Proteína HMGB1/metabolismo , Hematoma Subdural Crônico/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Idoso , Idoso de 80 Anos ou mais , Endotélio Vascular/metabolismo , Feminino , Proteína HMGB1/genética , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-6/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , Transdução de Sinais , Receptor 4 Toll-Like/genética
6.
Am J Med Sci ; 360(2): 176-191, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32553747

RESUMO

BACKGROUND: This study aimed to investigate the role of Clostridium butyricum (C. butyricum) in conjunction with the Toll-like receptor2 (TLR2) signaling pathway and T helper 17 (Th17) cells in dextran sodium sulfate (DSS)-induced colitis in mice. METHODS: Forty 8-week-old BALB/c mice were randomly divided into 5 groups of 8 mice for 7 days: control, DSS (5% DSS), DSS+C. butyricum (1 × 109 CFU), DSS+C. butyricum (1 × 108 CFU) and DSS+C. butyricum (1 × 107 CFU) groups. We assessed the disease activity index (DAI) and histological damage scores. The expression levels of TLR2, myeloid differentiation factor 88 (MyD88), nuclear factor kappa-B p65 (NF-κBp65), interleukin (IL) 17 (IL17), IL23 and retineic acid receptor related orphan nuclear receptor gamma t (RORγt) were determined through immunohistochemical staining, western blot and quantitative real-time PCR (qRT-PCR). The expression levels of CD3+CD4+IL17+ cells in peripheral blood were measured by flow cytometry. RESULTS: C. butyricum dose-dependently decreased DAI and histological damage scores in DSS mice and down-regulated the mRNA and protein levels of TLR2, MyD88 and NF-κBp65 in mouse colon tissue (all P < 0.05). In addition, C. butyricum dose-dependently decreased the levels of CD3+CD4+IL17+ cells in peripheral blood and down-regulated the mRNA and protein levels of IL17, IL23 and RORγt in mouse colon tissue (all P < 0.05). Moreover, the effect of C. butyricum on TLR2 was positively correlated with IL17, IL23 and RORγt. CONCLUSIONS: C. butyricum exerts a dose-dependently protective effect on acute intestinal inflammation induced by DSS in mice, by inhibiting the TLR2 signaling pathway, down-regulating the expression of IL23 and RORγt, and inhibiting the secretion of IL17.


Assuntos
Clostridium butyricum , Colite/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Probióticos , Células Th17/imunologia , Receptor 2 Toll-Like/imunologia , Fator de Transcrição RelA/imunologia , Animais , Peso Corporal , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Comportamento de Ingestão de Líquido , Comportamento Alimentar , Feminino , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/genética , Interleucina-23/imunologia , Interleucina-23/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , RNA Mensageiro/metabolismo , Distribuição Aleatória , Transdução de Sinais , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
7.
Am J Physiol Renal Physiol ; 319(1): F8-F18, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421349

RESUMO

Sepsis is the leading cause of acute kidney injury in critically ill patients. Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of septic kidney injury; however, the sites and mechanisms of renal TNF-α production during sepsis remain to be defined. In the present study, we showed that TNF-α expression is increased in medullary thick ascending limbs (MTALs) of mice with sepsis induced by cecal ligation and puncture. Treatment with lipopolysaccharide (LPS) for 3 h in vitro also increased MTAL TNF-α production. Sepsis and LPS increased MTAL TNF-α expression through activation of the myeloid differentiation factor 88 (MyD88)-IL-1 receptor-associated kinase 1-ERK signaling pathway. Pretreatment with monophosphoryl lipid A (MPLA), a nontoxic immunomodulator that protects against bacterial infection, eliminated the sepsis- and LPS-induced increases in MTAL TNF-α production. The suppressive effect of MPLA on TNF-α was mediated through activation of a phosphatidylinositol 3-kinase-dependent pathway that inhibits MyD88-dependent ERK activation. This likely involves MPLA-phosphatidylinositol 3-kinase-mediated induction of Tollip, which negatively regulates the MyD88-ERK pathway by inhibiting activation of IL-1 receptor-associated kinase 1. These regulatory mechanisms are similar to those previously shown to mediate the effect of MPLA to prevent sepsis-induced inhibition of MTAL [Formula: see text] absorption. These results identify the MTAL as a site of local TNF-α production in the kidney during sepsis and identify molecular mechanisms that can be targeted to attenuate renal TNF-α expression. The ability of MPLA pretreatment to suppress MyD88-dependent ERK signaling in the MTAL during sepsis has the dual beneficial effects of protecting tubule transport functions and attenuating harmful proinflammatory responses.


Assuntos
Citocinas/metabolismo , Medula Renal/efeitos dos fármacos , Lipídeo A/análogos & derivados , Alça do Néfron/efeitos dos fármacos , Sepse/metabolismo , Animais , Medula Renal/metabolismo , Lipídeo A/farmacologia , Lipopolissacarídeos/farmacologia , Alça do Néfron/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
PLoS Pathog ; 16(5): e1008188, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32365080

RESUMO

As a canonical adaptor for the Toll-like receptor (TLR) family, myeloid differentiation primary response protein 88 (MyD88) has crucial roles in host defense against infection by microbial pathogens, and its dysregulation might induce autoimmune diseases. Here, we demonstrate that the chicken Cullin 3-based ubiquitin ligase adaptor Speckle-type BTB-POZ protein (chSPOP) recognizes the intermediate domain of chicken MyD88 (chMyD88) and degrades it through the proteasome pathway. Knockdown or genetic ablation of chSPOP leads to aberrant elevation of chMyD88 protein. Through this interaction, chSPOP negatively regulates NF-κB pathway activity and thus the production of IL-1ß upon LPS challenge in chicken macrophages. Furthermore, Spop-deficient mice are more susceptible to infection with Salmonella typhimurium. Collectively, these findings demonstrate MyD88 as a bona fide substrate of SPOP and uncover a mechanism by which SPOP regulates MyD88 abundance and disease susceptibility.


Assuntos
Fator 88 de Diferenciação Mieloide/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células CHO , Galinhas/metabolismo , Cricetulus , Proteínas Culina/metabolismo , Células HeLa , Humanos , Imunidade Inata/fisiologia , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/fisiologia , Proteínas Nucleares/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteostase/fisiologia , Proteínas Repressoras/fisiologia , Transdução de Sinais , Ubiquitina/metabolismo , Ubiquitinação
9.
Zhongguo Zhong Yao Za Zhi ; 45(3): 602-608, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32237519

RESUMO

The aim of this paper was to observe the effect of Di'ao Xinxuekang(DXXK) on TLR4/MyD88/NF-κB signaling pathway in atherosclerotic rats, and to explore its anti-atherosclerotic mechanism. Sixty SD rats were randomly divided into normal group, model group, atorvastatin group(4.0 mg·kg~(-1)), and DXXK groups(100, 30, 10 mg·kg~(-1)), with 10 rats in each group. The atherosclerosis model was induced by high fat diet plus vitamin D_2. Experimental drugs were administered intragastrically once daily for 8 weeks starting from the 9 th week. Biochemical analyzers were used to detect levels of triglyceride(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C) and high-density lipoprotein cholesterol(HDL-C) in blood lipid. The levels of serum tumor necrosis factor(TNF)-α, interleukin(IL)-6 and IL-1ß were detected by ELISA. Pathological changes of aortic tissues were observed by using Sudan Ⅳ and HE staining. The mRNA and protein expressions of TLR4, MyD88 and NF-κB p65 in aortic tissues were detected by RT-PCR and Western blot, respectively. As compared with the model group, TC, TG, and LDL-C levels in serum were significantly decreased, HDL-C content was significantly increased, and levels of TNF-α, IL-6, and IL-1ß in serum were significantly decreased in atorvastatin group and DXXK high and middle dose groups. Aortic lesions in atorvastatin group and DXXK group were significantly improved, and the mRNA and protein expressions of TLR4, MyD88, NF-κB p65 in the aorta were decreased. DXXK has a preventive and therapeutic effect on atherosclerosis in rats, and its mechanism may be related to inhibiting inflammatory reaction by regulating TLR4/MyD88/NF-κB signal transduction, thereby inhibiting the progression of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Transdução de Sinais , Animais , Aorta/patologia , Atorvastatina , Interleucina-6/sangue , Interleucina-8/sangue , Lipídeos/sangue , Fator 88 de Diferenciação Mieloide/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/sangue
10.
J Neuroimmunol ; 343: 577217, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32244040

RESUMO

Toll-like receptors (TLRs) are sensors of pathogen-associated molecules that trigger inflammatory signalling in innate immune cells including macrophages. All TLRs, with the exception of TLR3, promote intracellular signalling via recruitment of the myeloid differentiation factor 88 (MyD88) adaptor, while TLR3 signals via Toll-Interleukin-1 Receptor (TIR)-domain-containing adaptor-inducing interferon (IFN)-ß (TRIF) adaptor to induce MyD88-independent signalling. Furthermore, TLR4 can activate both MyD88-dependent and -independent signalling (via TRIF). The study aim was to decipher the impact of the highly purified plant-derived (phyto) cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), when delivered in isolation and in combination (1:1), on MyD88-dependent and -independent signalling in macrophages. We employed the use of the viral dsRNA mimetic poly(I:C) and endotoxin lipopolysaccharide (LPS), to induce viral TLR3 and bacterial TLR4 signalling in human Tamm-Horsfall protein-1 (THP-1)-derived macrophages, respectively. TLR3/TLR4 stimulation promoted the activation of interferon (IFN) regulatory factor 3 (IRF3) and TLR4 promoted the activation of nuclear factor (NF)-κB signalling, with downstream production of the type I IFN-ß, the chemokines CXCL10 and CXCL8, and cytokine TNF-α. THC and CBD (both at 10 µM) attenuated TLR3/4-induced IRF3 activation and induction of CXCL10/IFN-ß, while both phytocannabinoids failed to impact TLR4-induced IκB-α degradation and TNF-α/CXCL8 expression. The role of CB1, CB2 and PPARγ receptors in mediating the effect of THC and CBD on MyD88-independent signalling was investigated. TLRs are attractive therapeutic targets given their role in inflammation and initiation of adaptive immunity, and data herein indicate that both CBD and THC preferentially modulate TLR3 and TLR4 signalling via MyD88-independent mechanisms in macrophages. This offers mechanistic insight into the role of phytocannabinoids in modulating cellular inflammation.


Assuntos
Canabidiol/farmacologia , Dronabinol/farmacologia , Macrófagos/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 3 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Linhagem Celular , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Fator 88 de Diferenciação Mieloide/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 3 Toll-Like/imunologia , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo
11.
Immunity ; 52(5): 782-793.e5, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32272082

RESUMO

Splenic red pulp macrophages (RPMs) contribute to erythrocyte homeostasis and are required for iron recycling. Heme induces the expression of SPIC transcription factor in monocyte-derived macrophages and promotes their differentiation into RPM precursors, pre-RPMs. However, the requirements for differentiation into mature RPMs remain unknown. Here, we have demonstrated that interleukin (IL)-33 associated with erythrocytes and co-cooperated with heme to promote the generation of mature RPMs through activation of the MyD88 adaptor protein and ERK1/2 kinases downstream of the IL-33 receptor, IL1RL1. IL-33- and IL1RL1-deficient mice showed defective iron recycling and increased splenic iron deposition. Gene expression and chromatin accessibility studies revealed a role for GATA transcription factors downstream of IL-33 signaling during the development of pre-RPMs that retained full potential to differentiate into RPMs. Thus, IL-33 instructs the development of RPMs as a response to physiological erythrocyte damage with important implications to iron recycling and iron homeostasis.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/imunologia , Ferro/metabolismo , Macrófagos/imunologia , Transdução de Sinais/imunologia , Baço/metabolismo , Animais , Eritrócitos/imunologia , Eritrócitos/metabolismo , Heme/imunologia , Heme/metabolismo , Homeostase/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Macrófagos/metabolismo , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fator 88 de Diferenciação Mieloide/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Baço/citologia
12.
Nat Commun ; 11(1): 1978, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332737

RESUMO

There is the notion that infection with a virulent intestinal pathogen induces generally stronger mucosal adaptive immunity than the exposure to an avirulent strain. Whether the associated mucosal inflammation is important or redundant for effective induction of immunity is, however, still unclear. Here we use a model of auxotrophic Salmonella infection in germ-free mice to show that live bacterial virulence factor-driven immunogenicity can be uncoupled from inflammatory pathogenicity. Although live auxotrophic Salmonella no longer causes inflammation, its mucosal virulence factors remain the main drivers of protective mucosal immunity; virulence factor-deficient, like killed, bacteria show reduced efficacy. Assessing the involvement of innate pathogen sensing mechanisms, we show MYD88/TRIF, Caspase-1/Caspase-11 inflammasome, and NOD1/NOD2 nodosome signaling to be individually redundant. In colonized animals we show that microbiota metabolite cross-feeding may recover intestinal luminal colonization but not pathogenicity. Consequent immunoglobulin A immunity and microbial niche competition synergistically protect against Salmonella wild-type infection.


Assuntos
Imunidade nas Mucosas , Mucosa Intestinal/microbiologia , Infecções por Salmonella/microbiologia , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Antígenos de Bactérias , Caspase 1/metabolismo , Caspases Iniciadoras/metabolismo , Proliferação de Células , Microbioma Gastrointestinal , Imunidade Inata , Imunoglobulina A/imunologia , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Fator 88 de Diferenciação Mieloide/metabolismo , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Salmonella typhimurium/patogenicidade , Transdução de Sinais , Virulência , Fatores de Virulência
13.
Mol Cells ; 43(3): 251-263, 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32131150

RESUMO

Flagellin, a major structural protein of the flagellum found in all motile bacteria, activates the TLR5- or NLRC4 inflammasomedependent signaling pathway to induce innate immune responses. Flagellin can also serve as a specific antigen for the adaptive immune system and stimulate anti-flagellin antibody responses. Failure to recognize commensal-derived flagellin in TLR5-deficient mice leads to the reduction in antiflagellin IgA antibodies at steady state and causes microbial dysbiosis and mucosal barrier breach by flagellated bacteria to promote chronic intestinal inflammation. Despite the important role of anti-flagellin antibodies in maintaining the intestinal homeostasis, regulatory mechanisms underlying the flagellin-specific antibody responses are not well understood. In this study, we show that flagellin induces interferon-ß (IFN-ß) production and subsequently activates type I IFN receptor signaling in a TLR5- and MyD88-dependent manner in vitro and in vivo . Internalization of TLR5 from the plasma membrane to the acidic environment of endolysosomes was required for the production of IFN-ß, but not for other proinflammatory cytokines. In addition, we found that antiflagellin IgG2c and IgA responses were severely impaired in interferon-alpha receptor 1 (IFNAR1)-deficient mice, suggesting that IFN-ß produced by the flagellin stimulation regulates anti-flagellin antibody class switching. Our findings shed a new light on the regulation of flagellin-mediated immune activation and may help find new strategies to promote the intestinal health and develop mucosal vaccines.


Assuntos
Flagelina/farmacologia , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Interferon beta/biossíntese , Animais , Modelos Animais de Doenças , Flagelina/antagonistas & inibidores , Flagelina/imunologia , Flagelina/isolamento & purificação , Interferon beta/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor de Interferon alfa e beta/imunologia , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais , Receptor 5 Toll-Like/imunologia , Receptor 5 Toll-Like/metabolismo
14.
Phytomedicine ; 69: 153197, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146298

RESUMO

BACKGOUND: Ginsenoside Rb1, the main active constituent of Panax ginseng, displays significant anti-inflammatory activity, although the mechanism has not been clearly unraveled. In this study, Rb1's mechanism of anti-inflammatory effects were investigated. METHODS: The flow cytometry and enzyme-linked immunosorbent assay (ELISA) were empolyed to detect pro-inflammatory cytokines release. The related protein and gene expression was investigated by western blotting and qRT-PCR. The dimerization of TLR4 was measured by co-immunoprecipitation and molecular docking assays. Cellular thermal shift assay was used for the determination of the binding of Rb1 and TLR4. For animal moldels, LPS- or cantharidin-induced acute kidney injury, LPS-induced septic death, and dimethyl benzene-induced ear edema were employed to investigate Rb1's anti-inflammatory activity in vivo. RESULTS: Rb1 significantly decreased inflammatory cytokines release in LPS-stimulated RAW264.7 cells and BMDMs, as well as COX-2 and iNOS amounts. Rb1 reduced LPS-associated calcium influx, ROS production, and NO generation. The NF-κB and MAPK axes participated in Rb1's anti-inflammatory effects. Molecular docking simulation indicated Rb1 bound to TLR4 to prevent TLR4 dimerization, as confirmed by co-immunoprecipitation and cellular thermal shift assay. Furthermore, MyD88 recruitment and TAK1 expression were altered by reduced TLR4 dimerization, indicating the TLR4-MyD88-NF-κB/MAPK pathways contributed to Rb1's anti-inflammatory process. In animal models, Rb1 markedly alleviated LPS- or cantharidin-induced acute kidney injury, rescued LPS-induced septic mice from death, and inhibited dimethyl benzene-induced mouse ear edema. CONCLUSION: Overall, these findings demonstrate Rb1 exhibits marked anti-inflammatory effects, suggesting Rb1 represents an optimal molecule for treating inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ginsenosídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Cantaridina/toxicidade , Ginsenosídeos/química , Células HEK293 , Humanos , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Multimerização Proteica , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor 4 Toll-Like/química
15.
Proc Natl Acad Sci U S A ; 117(11): 6092-6102, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32127472

RESUMO

The KLHL14 gene acquires frequent inactivating mutations in mature B cell malignancies, especially in the MYD88L265P, CD79B mutant (MCD) genetic subtype of diffuse large B cell lymphoma (DLBCL), which relies on B cell receptor (BCR) signaling for survival. However, the pathogenic role of KLHL14 in DLBCL and its molecular function are largely unknown. Here, we report that KLHL14 is in close proximity to the BCR in the endoplasmic reticulum of MCD cell line models and promotes the turnover of immature glycoforms of BCR subunits, reducing total cellular BCR levels. Loss of KLHL14 confers relative resistance to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and promotes assembly of the MYD88-TLR9-BCR (My-T-BCR) supercomplex, which initiates prosurvival NF-κB activation. Consequently, KLHL14 inactivation allows MCD cells to maintain NF-κB signaling in the presence of ibrutinib. These findings reinforce the central role of My-T-BCR-dependent NF-κB signaling in MCD DLBCL and suggest that the genetic status of KLHL14 should be considered in clinical trials testing inhibitors of BTK and BCR signaling mediators in DLBCL.


Assuntos
Proteínas de Transporte/genética , Genes Supressores de Tumor , Linfoma Difuso de Grandes Células B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo , Antígenos CD79/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Retículo Endoplasmático/metabolismo , Células HEK293 , Humanos , Linfoma Difuso de Grandes Células B/patologia , Mutagênese Sítio-Dirigida , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Proteólise , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
16.
PLoS One ; 15(3): e0230718, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210474

RESUMO

Chlamydia trachomatis is the most common bacterial sexually-transmitted infection and the major cause of preventable blindness worldwide. The asymptomatic nature of many infections along with uncontrolled inflammation leads to irreversible damage in the upper genital tract and the tarsal conjunctivae, with the major complications of infertility and chronic pelvic pain, and blindness, respectively. Inflammation must, therefore, be tightly regulated to avoid an unrestrained immune response. The genetic factors that regulate inflammation through Toll-like receptor (TLR) signaling pathways during C. trachomatis infection have not been fully characterized. SIGIRR (also known as IL-1R8 or TIR8) can regulate inflammation in response to various pathogens and diseases. However, nothing is known about its role during C. trachomatis infection. Expression of the pro-inflammatory chemokine, IL-8, was measured in epithelial cells infected with C. trachomatis. The effect of SIGIRR was determined by depleting SIGIRR or over-expressing SIGIRR in the epithelial cells before infection. Our results indicate that, in the absence of SIGIRR, epithelial cells induce higher levels of the pro-inflammatory chemokine, IL-8, in response to C. trachomatis infection. In addition, SIGIRR associates with MyD88 in both infected and uninfected infected cells. Collectively, our data demonstrate that SIGIRR functions as a negative regulator of the immune response to C. trachomatis infection. This finding provides insights into the immuno-pathogenesis of C. trachomatis that can be used to treat and identify individuals at risk of uncontrolled inflammation during infection.


Assuntos
Chlamydia trachomatis/fisiologia , Receptores de Interleucina-1/metabolismo , Receptores Toll-Like/metabolismo , Chlamydia trachomatis/imunologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Regulação da Expressão Gênica/imunologia , Inativação Gênica , Células HeLa , Humanos , Interleucina-8/genética , Fator 88 de Diferenciação Mieloide/metabolismo , RNA Mensageiro/genética , Receptores de Interleucina-1/deficiência , Receptores de Interleucina-1/genética
17.
J Virol ; 94(10)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32161170

RESUMO

Kaposi sarcoma-associated herpesvirus (KSHV) is necessary but not sufficient for primary effusion lymphoma (PEL) development. Alterations in cellular signaling pathways are also a characteristic of PEL. Other B cell lymphomas have acquired an oncogenic mutation in the myeloid differentiation primary response 88 (MYD88) gene. The MYD88 L265P mutant results in the activation of interleukin-1 receptor associated kinase (IRAK). To probe IRAK/MYD88 signaling in PEL, we employed CRISPR/Cas9 technology to generate stable deletion clones in BCBL-1Cas9 and BC-1Cas9 cells. To look for off-target effects, we determined the complete exome of the BCBL-1Cas9 and BC-1Cas9 cells. Deletion of either MYD88, IRAK4, or IRAK1 abolished interleukin-1 beta (IL-1ß) signaling; however, we were able to grow stable subclones from each population. Transcriptome sequencing (RNA-seq) analysis of IRAK4 knockout cell lines (IRAK4 KOs) showed that the IRAK pathway induced cellular signals constitutively, independent of IL-1ß stimulation, which was abrogated by deletion of IRAK4. Transient complementation with IRAK1 increased NF-κB activity in MYD88 KO, IRAK1 KO, and IRAK4 KO cells even in the absence of IL-1ß. IL-10, a hallmark of PEL, was dependent on the IRAK pathway, as IRAK4 KOs showed reduced IL-10 levels. We surmise that, unlike B cell receptor (BCR) signaling, MYD88/IRAK signaling is constitutively active in PEL, but that under cell culture conditions, PEL rapidly became independent of this pathway.IMPORTANCE One hundred percent of primary effusion lymphoma (PEL) cases are associated with Kaposi sarcoma-associated herpesvirus (KSHV). PEL cell lines, such as BCBL-1, are the workhorse for understanding this human oncovirus and the host pathways that KSHV dysregulates. Understanding their function is important for developing new therapies as well as identifying high-risk patient groups. The myeloid differentiation primary response 88 (MYD88)/interleukin-1 receptor associated kinase (IRAK) pathway, which has progrowth functions in other B cell lymphomas, has not been fully explored in PEL. By performing CRISPR/Cas9 knockout (KO) studies targeting the IRAK pathway in PEL, we were able to determine that established PEL cell lines can circumvent the loss of IRAK1, IRAK4, and MYD88; however, the deletion clones are deficient in interleukin-10 (IL-10) production. Since IL-10 suppresses T cell function, this suggests that the IRAK pathway may serve a function in vivo and during early-stage development of PEL.


Assuntos
Herpesvirus Humano 8/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Linfoma de Efusão Primária/metabolismo , Linfoma de Efusão Primária/virologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/genética , Linfócitos B , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Herpesvirus Humano 8/fisiologia , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Análise de Sequência , Transcriptoma
18.
Curr Med Sci ; 40(1): 130-137, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32166675

RESUMO

Sinomenine (SN) has been used in the clinical treatment of systemic lupus erythematosus and rheumatoid arthritis for many years. Studies showed that SN held protective effects such as anti-inflammation, scavenging free radicals and suppressing immune response in many autoimmune diseases. The purpose of the present study is to explore the mechanism of anti-inflammation of SN on lipopolysaccharide (LPS)-induced macrophages activation and investigate whether the TLR4/NF-κB signaling pathway participated in. Macrophages isolated from mouse peritoneal cavity were stimulated by 1 µg/mL LPS for 24 h. And then the cells were treated with various concentrations of SN, TLR4 inhibitor respectively for additional 48 h. Drug toxicity was detected by MTT assay and Transwell experiment was used to assess chemotaxis. Furthermore, TLR4 and MyD88 mRNA levels were detected by real-time PCR. Western blotting was used to examine TLR4, MyD88 and phosphorylated IκB protein expression in macrophages. Immunofluorescence assay was applied to observe p65 NF-κB protein expression in macrophage nucleus. We extracted macrophages with high purity and activity from the abdominal cavity of mice. SN remarkably inhibited the chemotaxis and secretion function of LPS-stimulated macrophages. It also down-regulated both the protein levels of inflammatory cytokines (TNF-α, IL-1ß and IL-6) and the RNA and protein levels of the key factors (TLR4, MyD88, P-IκB) in TLR4 pathway. The expression of p65 NF-κB protein in nuclei was down-regulated, which was correlated with a similar decrease in P-IκB protein level. In conclusion, SN can inhibit the LPS induced immune responses in macrophages by blocking the activated TLR4/NF-κB signaling pathway. These results may provide a therapeutic approach to regulate inflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Lipopolissacarídeos/efeitos adversos , Macrófagos/citologia , Morfinanos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
19.
Biomed Pharmacother ; 124: 109883, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32004938

RESUMO

Intestinal mucositis causes great suffering to cancer patients who undergo chemotherapy and radiotherapy. Owing to the uncertain side effects of anticancer drugs to attenuate patients' intestinal mucositis, many studies focused on traditional Chinese medicine (TCM). Patchouli alcohol (PA) is an active compound extracted from Pogostemon cablin, and has potent gastrointestinal protective effect. However, whether PA has an effect on intestinal mucositis is still unknown. Therefore, we established a rat model of intestinal mucositis via intraperitoneal injection of 5-fluorouracil, and intragastrically administrated PA (10, 20, and 40 mg/kg) to evaluate the effect of PA on intestinal mucositis. The routine observation (body weight, food intake, and diarrhea) in rats was used to detect whether PA had an effect on intestinal mucositis. Levels of inflammatory cytokines (TNF-α, IL-1ß, IL-6, IL-10, and MPO), mucosal barrier proteins (zonula occludens -1 (ZO-1), claudin-1, occludin, myosin light chain (MLC), and mucin-2) and intestinal microbiota were determined to elucidate the underlying mechanism of PA action on intestinal mucositis in rats. The results showed that PA could effectively improve body weight, food intake, and diarrhea in intestinal mucositis rats, preliminary confirming PA efficacy. Further experiments revealed that PA not only decreased the levels of TNF-α, IL-1ß, IL-6, and MPO but also increased the level of IL-10 significantly. In addition, the expression of mucosal barrier proteins and microbiota community were also improved after PA treatment in diseased rats. Hence, PA may prevent the development and progression of intestinal mucositis by improving inflammation, protecting mucosal barrier, and regulating intestinal microbiota.


Assuntos
Fluoruracila/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosite/prevenção & controle , Sesquiterpenos/farmacologia , Animais , Antimetabólitos Antineoplásicos/toxicidade , Relação Dose-Resposta a Droga , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Mucosa Intestinal/patologia , Masculino , Mucosite/induzido quimicamente , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 2 Toll-Like/metabolismo
20.
Immunogenetics ; 72(3): 181-203, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32002590

RESUMO

Toll-interleukin-1R resistance (TIR) domains are ubiquitously present in all forms of cellular life. They are most commonly found in signaling proteins, as units responsible for signal-dependent formation of protein complexes that enable amplification and spatial propagation of the signal. A less common function of TIR domains is their ability to catalyze nicotinamide adenine dinucleotide degradation. This survey analyzes 26,414 TIR domains, automatically classified based on group-specific sequence patterns presumably determining biological function, using a statistical approach termed Bayesian partitioning with pattern selection (BPPS). We examine these groups and patterns in the light of available structures and biochemical analyses. Proteins within each of thirteen eukaryotic groups (10 metazoans and 3 plants) typically appear to perform similar functions, whereas proteins within each prokaryotic group typically exhibit diverse domain architectures, suggesting divergent functions. Groups are often uniquely characterized by structural fold variations associated with group-specific sequence patterns and by herein identified sequence motifs defining TIR domain functional divergence. For example, BPPS identifies, in helices C and D of TIRAP and MyD88 orthologs, conserved surface-exposed residues apparently responsible for specificity of TIR domain interactions. In addition, BPPS clarifies the functional significance of the previously described Box 2 and Box 3 motifs, each of which is a part of a larger, group-specific block of conserved, intramolecularly interacting residues.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Domínios Proteicos/genética , Domínios Proteicos/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Animais , Teorema de Bayes , Bases de Dados Genéticas , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Humanos , Interleucinas , Modelos Moleculares , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Estrutura Secundária de Proteína , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
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