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1.
J Clin Invest ; 132(5)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35077396

RESUMO

Anti-TNF antibodies are effective for treating patients with inflammatory bowel disease (IBD), but many patients fail to respond to anti-TNF therapy, highlighting the importance of TNF-independent disease. We previously demonstrated that acute deletion of 2 IBD susceptibility genes, A20 (Tnfaip3) and Abin-1 (Tnip1), in intestinal epithelial cells (IECs) sensitized mice to both TNF-dependent and TNF-independent death. Here we show that TNF-independent IEC death after A20 and Abin-1 deletion was rescued by germ-free derivation or deletion of MyD88, while deletion of Trif provided only partial protection. Combined deletion of Ripk3 and Casp8, which inhibits both apoptotic and necroptotic death, completely protected against death after acute deletion of A20 and Abin-1 in IECs. A20- and Abin-1-deficient IECs were sensitized to TNF-independent, TNFR1-mediated death in response to lymphotoxin α (LTα) homotrimers. Blockade of LTα in vivo reduced weight loss and improved survival when combined with partial deletion of MyD88. Biopsies of inflamed colon mucosa from patients with IBD exhibited increased LTA and IL1B expression, including a subset of patients with active colitis on anti-TNF therapy. These data show that microbial signals, MyD88, and LTα all contribute to TNF-independent intestinal injury.


Assuntos
Doenças Inflamatórias Intestinais , Linfotoxina-alfa , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose , Células Epiteliais/metabolismo , Epitélio/metabolismo , Humanos , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/metabolismo , Linfotoxina-alfa/genética , Linfotoxina-alfa/metabolismo , Linfotoxina-alfa/farmacologia , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Inibidores do Fator de Necrose Tumoral
2.
Adv Immunol ; 148: 1-48, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33190732

RESUMO

A20/TNFAIP3 is a TNF induced gene that plays a profound role in preserving cellular and organismal homeostasis (Lee, et al., 2000; Opipari etal., 1990). This protein has been linked to multiple human diseases via genetic, epigenetic, and an emerging series of patients with mono-allelic coding mutations. Diverse cellular functions of this pleiotropically expressed protein include immune-suppressive, anti-inflammatory, and cell protective functions. The A20 protein regulates ubiquitin dependent cell signals; however, the biochemical mechanisms by which it performs these functions is surprisingly complex. Deciphering these cellular and biochemical facets of A20 dependent biology should greatly improve our understanding of murine and human disease pathophysiology as well as unveil new mechanisms of cell and tissue biology.


Assuntos
Inflamação/imunologia , Mutação/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Animais , Autoimunidade , Morte Celular , Homeostase , Humanos , Camundongos
3.
Nat Immunol ; 21(4): 422-433, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32205880

RESUMO

A20 is an anti-inflammatory protein that is strongly linked to human disease. Here, we find that mice expressing three distinct targeted mutations of A20's zinc finger 7 (ZF7) ubiquitin-binding motif uniformly developed digit arthritis with features common to psoriatic arthritis, while mice expressing point mutations in A20's OTU or ZF4 motifs did not exhibit this phenotype. Arthritis in A20ZF7 mice required T cells and MyD88, was exquisitely sensitive to tumor necrosis factor and interleukin-17A, and persisted in germ-free conditions. A20ZF7 cells exhibited prolonged IκB kinase activity that drove exaggerated transcription of late-phase nuclear factor-κB response genes in vitro and in prediseased mouse paws in vivo. In addition, mice expressing double-mutant A20 proteins in A20's ZF4 and ZF7 motifs died perinatally with multi-organ inflammation. Therefore, A20's ZF4 and ZF7 motifs synergistically prevent inflammatory disease in a non-catalytic manner.


Assuntos
Artrite Psoriásica/metabolismo , Inflamação/metabolismo , Ubiquitina/metabolismo , Animais , Células Cultivadas , Interleucina-17 , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , NF-kappa B/metabolismo , Ligação Proteica/fisiologia , Transdução de Sinais/fisiologia , Transcrição Gênica/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação/fisiologia , Dedos de Zinco/fisiologia
5.
Nat Commun ; 5: 5494, 2014 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-25417649

RESUMO

The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is downregulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. Here we show that RXRα overexpression or ligand activation increases host susceptibility to viral infections in vitro and in vivo, while Rxra-/- or antagonist treatment reduces infection by the same viruses. Consistent with these functional studies, ligand activation of RXR inhibits the expression of antiviral genes including type I interferon (IFN) and Rxra-/- macrophages produce more IFNß than WT macrophages in response to polyI:C stimulation. Further results indicate that ligand activation of RXR suppresses the nuclear translocation of ß-catenin, a co-activator of IFNß enhanceosome. Thus, our studies have uncovered a novel RXR-dependent innate immune regulatory pathway, suggesting that the downregulation of RXR expression or RXR antagonist treatment benefits host antiviral response, whereas RXR agonist treatment may increase the risk of viral infections.


Assuntos
Herpesvirus Humano 1/imunologia , Interferon beta/antagonistas & inibidores , Receptor X Retinoide alfa/genética , Vírus da Estomatite Vesicular Indiana/imunologia , Transporte Ativo do Núcleo Celular , Animais , Linhagem Celular , Regulação para Baixo , Ácidos Graxos Insaturados/farmacologia , Células HEK293 , Herpes Simples/imunologia , Humanos , Interferon beta/imunologia , Ligantes , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poli I-C/farmacologia , Interferência de RNA , RNA Interferente Pequeno , Receptor X Retinoide alfa/antagonistas & inibidores , Receptor X Retinoide alfa/biossíntese , Tetra-Hidronaftalenos/farmacologia , Estomatite Vesicular/imunologia , Ensaio de Placa Viral , beta Catenina/metabolismo
6.
CNS Spectr ; 19(4): 282-92, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24354998

RESUMO

This article reviews the literature regarding the impact of cosmetic surgery on health-related quality of life (QOL). Studies were identified through PubMed/Medline and PsycINFO searches from January 1960 to December 2011. Twenty-eight studies were included in this review, according to specific selection criteria. The procedures and tools employed in cosmetic surgery research studies were remarkably diverse, thus yielding difficulties with data analysis. However, data indicate that individuals undergoing cosmetic surgery began with lower values on aspects of QOL than control subjects, and experienced significant QOL improvement post-procedurally, an effect that appeared to plateau with time. Despite the complexity of measuring QOL in cosmetic surgery patients, most studies showed an improvement in QOL after cosmetic surgery procedures. However, this finding was clouded by measurement precision as well as heterogeneity of procedures and study populations. Future research needs to focus on refining measurement techniques, including developing cosmetic surgery-specific QOL measures.


Assuntos
Técnicas Cosméticas/psicologia , Qualidade de Vida/psicologia , Abdominoplastia , Blefaroplastia , Humanos , Lipectomia , Mamoplastia , Procedimentos Cirúrgicos Ortognáticos , Rinoplastia , Ritidoplastia
7.
Immunol Rev ; 244(1): 44-54, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22017430

RESUMO

Nuclear-factor κB (NF-κB) transcription factors are activated by a wide variety of stimuli in diverse cell types and control key aspects of immune function and development. Receptor-mediated activation of NF-κB appears to occur through two distinct signaling pathways termed as the canonical and non-canonical NF-κB pathways. Although much work has demonstrated the physiological importance of non-canonical NF-κB signaling to immunity and its involvement in diverse pathologies, such as cancers and autoimmune disease, the architecture and regulation of the pathway is only beginning to be understood. The non-canonical pathway appears to be activated by a select set of receptors within the tumor necrosis factor superfamily, and we discuss the molecular mechanisms that connect ligation of these receptors to pathway activation. It has become increasingly clear that the key regulatory step of the pathway involves modulation of the post-translational degradation of NF-κB-inducing kinase (NIK), the central activating kinase of non-canonical NF-κB signaling. How NIK post-translational stability is controlled before and after receptor ligation is an important aspect of understanding non-canonical NF-κB signaling. Furthermore, how release of NF-κB dimers downstream of the pathway's activation is actually connected to its identified physiological and pathological roles is a key remaining question in the field.


Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata , NF-kappa B/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Transdução de Sinais/imunologia , Fator 2 Associado a Receptor de TNF/imunologia , Fator 3 Associado a Receptor de TNF/imunologia , Animais , Dimerização , Estabilidade Enzimática , Humanos , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/imunologia , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Quinase Induzida por NF-kappaB
8.
Curr Top Microbiol Immunol ; 349: 115-43, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-20848362

RESUMO

Members of the NF-κB transcription factor family play a critical role in the development of innate immunity. Upon recognition of pathogen infections or tissue damage, the NF-κB pathway is strongly activated by cellular pattern recognition receptors, including Toll-like receptors and multiple cytosolic receptors such as RIG-I-like helicases and NOD family proteins. NF-κB is required not only for the expression, but also for subsequent signal transduction of numerous downstream cytokines. NF-κB-responsive genes affect a diverse array of cellular processes including apoptosis and cell survival, and often directly control the course of a pathogen infection. In this review, we will examine signaling pathways leading to NF-κB activation during the innate immune response and mechanisms of pathogen-modulation of these pathways; the specifics of NF-κB-dependent gene programs, and the physiological consequences for the immune system caused by the absence of individual NF-κB subunits.


Assuntos
Imunidade Inata , NF-kappa B/fisiologia , Animais , Genoma Viral , Humanos , Interferon beta/genética , Subunidade p40 da Interleucina-12/genética , Multimerização Proteica , Receptores Toll-Like/fisiologia
9.
Sci Signal ; 3(138): pe29, 2010 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-20823402

RESUMO

Although NF-kappaB (nuclear factor kappaB) was discovered less than 25 years ago, it is one of the most well-studied transcription factors. It plays critical roles in various immune and cellular processes, and its dysregulation is a major driver of cancer and inflammatory pathology. A new book published by Cold Spring Harbor Laboratory Press, NF-kappaB: A Network Hub Controlling Immunity, Inflammation, and Cancer, provides a series of excellent reviews on the architecture, regulation, and pathophysiological roles of NF-kappaB signaling by some of the leading investigators in the field.


Assuntos
Adaptação Fisiológica , NF-kappa B/fisiologia , Humanos , Imunidade Inata , NF-kappa B/imunologia , Transdução de Sinais
10.
Sci Signal ; 3(123): ra41, 2010 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-20501937

RESUMO

Canonical and noncanonical nuclear factor kappaB (NF-kappaB) signaling are the two basic pathways responsible for the release of NF-kappaB dimers from their inhibitors. Enhanced NF-kappaB signaling leads to inflammatory and proliferative diseases; thus, inhibitory pathways that limit its activity are critical. Whereas multiple negative feedback mechanisms control canonical NF-kappaB signaling, none has been identified for the noncanonical pathway. Here, we describe a mechanism of negative feedback control of noncanonical NF-kappaB signaling that attenuated the stabilization of NF-kappaB-inducing kinase (NIK), the central regulatory kinase of the noncanonical pathway, induced by B cell-activating factor receptor (BAFF-R) and lymphotoxin beta receptor (LTbetaR). Inhibitor of kappaB (IkappaB) kinase alpha (IKKalpha) was previously thought to lie downstream of NIK in the noncanonical NF-kappaB pathway; we showed that phosphorylation of NIK by IKKalpha destabilized NIK. In the absence of IKKalpha-mediated negative feedback, the abundance of NIK increased after receptor ligation. A form of NIK with mutations in the IKKalpha-targeted serine residues was more stable than wild-type NIK and resulted in increased noncanonical NF-kappaB signaling. Thus, in addition to the regulation of the basal abundance of NIK in unstimulated cells by a complex containing tumor necrosis factor receptor-associated factor (TRAF) and cellular inhibitor of apoptosis (cIAP) proteins, IKKalpha-dependent destabilization of NIK prevents the uncontrolled activity of the noncanonical NF-kappaB pathway after receptor ligation.


Assuntos
Retroalimentação Fisiológica/fisiologia , Quinase I-kappa B/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Animais , Receptor do Fator Ativador de Células B/metabolismo , Western Blotting , Linhagem Celular , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Quinase I-kappa B/genética , Imunoprecipitação , Proteínas Inibidoras de Apoptose/metabolismo , Receptor beta de Linfotoxina/metabolismo , Camundongos , Mutação , NF-kappa B/genética , Fosforilação , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Serina/genética , Serina/metabolismo , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Transfecção , Quinase Induzida por NF-kappaB
11.
J Leukoc Biol ; 82(2): 187-95, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17314330

RESUMO

The immune system modulates a number of biological processes to properly defend against pathogens. Here, we review how crosstalk between nuclear hormone receptors and the innate immune system may influence multiple biological functions during an immune response. Although nuclear hormone receptor repression of innate immune responses and inflammation has been well studied, a number of new studies have identified repression of nuclear hormone receptor signaling by various innate immune responses. IFN regulatory factor 3, a key transcription factor involved in the induction of antiviral genes, may play a role in mediating such crosstalk between the innate immune response and nuclear receptor-regulated metabolism. This crosstalk mechanism is now implicated in the pathogenesis of atherosclerosis and Reye's syndrome and could provide an explanation for other pathogen-associated metabolic and developmental disorders.


Assuntos
Imunidade Inata , Doenças Metabólicas/imunologia , Receptores Citoplasmáticos e Nucleares/imunologia , Animais , Previsões , Humanos , Fator Regulador 3 de Interferon/imunologia , Doenças Metabólicas/patologia , Modelos Imunológicos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptor X Retinoide alfa/imunologia
12.
Proc Natl Acad Sci U S A ; 99(25): 16081-6, 2002 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-12444263

RESUMO

Steroid receptor RNA activator (SRA) is an RNA transcript that functions as a eukaryotic transcriptional coactivator for steroid hormone receptors. We report here the isolation and functional characterization of distinct RNA substructures within the SRA molecule that constitute its coactivation function. We used comparative sequence analysis and free energy calculations to systematically study SRA RNA subdomains for identification of structured regions and base pairings, and we used site-directed mutagenesis to assess their functional consequences. Together with genetic deletion analysis, this approach identified six RNA motifs in SRA important for coactivation. Because all nucleotide changes in the mutants that disrupted SRA function were silent mutations presumed not to alter deduced encoded amino acid sequence, our analysis provides strong evidence that SRA-mediated coactivation is executed by distinct RNA motifs and not by an encoded protein.


Assuntos
RNA não Traduzido/química , Receptores de Esteroides/fisiologia , Animais , Pareamento de Bases , Células HeLa , Humanos , Camundongos , Modelos Moleculares , Mutação , Conformação de Ácido Nucleico , RNA Longo não Codificante , RNA não Traduzido/genética , RNA não Traduzido/fisiologia , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Relação Estrutura-Atividade , Transcrição Gênica , Transfecção
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