RESUMEN
More severe atopic dermatitis and psoriasis are associated with a higher cumulative impact on quality of life, multimorbidity and healthcare costs. Proactive, early intervention in those most at risk of severe disease may reduce this cumulative burden and modify the disease trajectory to limit progression. The lack of reliable biomarkers for this at-risk group represents a barrier to such a paradigm shift in practice. To expedite discovery and validation, the BIOMarkers in Atopic Dermatitis and Psoriasis (BIOMAP) consortium (a large-scale European, interdisciplinary research initiative) has curated clinical and molecular data across diverse study designs and sources including cross-sectional and cohort studies (small-scale studies through to large multicentre registries), clinical trials, electronic health records and large-scale population-based biobanks. We map all dataset disease severity instruments and measures to three key domains (symptoms, inflammatory activity and disease course), and describe important codependencies and relationships across variables and domains. We prioritize definitions for more severe disease with reference to international consensus, reference standards and/or expert opinion. Key factors to consider when analysing datasets across these diverse study types include explicit early consideration of biomarker purpose and clinical context, candidate biomarkers associated with disease severity at a particular point in time and over time and how they are related, taking the stage of biomarker development into account when selecting disease severity measures for analyses, and validating biomarker associations with disease severity outcomes using both physician- and patient-reported measures and across domains. The outputs from this exercise will ensure coherence and focus across the BIOMAP consortium so that mechanistic insights and biomarkers are clinically relevant, patient-centric and more generalizable to current and future research efforts.
Atopic dermatitis (AD), and psoriasis are long-term skin conditions that can significantly affect people's lives, especially when symptoms are severe. Approximately 10% of adults and 20% of children are affected by AD, while psoriasis affects around 5% of people in the UK. Both conditions are associated with debilitating physical symptoms (such as itch) and have been linked to depression and anxiety. Biomarkers are naturally occurring chemicals in the human body and have potential to enhance the longer-term management of AD and psoriasis. Currently, there are no routinely used biomarkers that can identify people who experience or will go on to develop severe AD and psoriasis. For this reason, research is under way to understand which biomarkers are linked to severity. In this study, a multidisciplinary team of skin researchers from across Europe, along with patient groups, discussed the complexities of studying severity-related biomarkers. We identified a number of severity measurement approaches and there were recommendations for future biomarker research, including (i) considering multiple measures as no single measure can encompass all aspects of severity, (ii) exploring severity measures recorded by both healthcare professionals and patients, as each may capture different aspects, and (iii) accounting for influencing factors, such as different treatment approaches, that may impact AD and psoriasis severity, which make it challenging to compare findings across studies. Overall, we anticipate that the insights gained from these discussions will increase the likelihood of biomarkers being effectively applied in real-world settings, to ultimately improve outcomes for people with AD and psoriasis.
Asunto(s)
Biomarcadores , Dermatitis Atópica , Psoriasis , Índice de Severidad de la Enfermedad , Humanos , Psoriasis/inmunología , Psoriasis/diagnóstico , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/inmunología , Investigación InterdisciplinariaRESUMEN
BACKGROUND: Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. OBJECTIVES: To perform a scoping review to identify and catalogue candidate biomarkers of systemic treatment response in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with systemic treatment response. The main outcomes were any measure of systemic treatment efficacy or safety. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise and mapped to relevant cellular and molecular pathways. RESULTS: Of 71 included studies (67 studying effectiveness outcomes and eight safety outcomes; four studied both), most reported genomic or proteomic biomarkers associated with response to biologics (48 studies). Methodological or reporting limitations frequently compromised the interpretation of findings, including inadequate control for key covariates, lack of adjustment for multiple testing, and selective outcome reporting. We identified candidate biomarkers of efficacy to tumour necrosis factor inhibitors [variation in CARD14, CDKAL1, IL1B, IL12B and IL17RA loci, and lipopolysaccharide-induced phosphorylation of nuclear factor (NF)-κB in type 2 dendritic cells] and ustekinumab (HLA-C*06:02 and variation in an IL1B locus). None were supported by sufficient evidence for clinical use without further validation studies. Candidate biomarkers were found to be involved in the immune cellular crosstalk implicated in psoriasis pathogenesis, most notably antigen presentation, T helper (Th)17 cell differentiation, positive regulation of NF-κB, and Th17 cell activation. CONCLUSIONS: This comprehensive catalogue provides a key resource for researchers and reveals a diverse range of biomarker types and outcomes in the included studies. The candidate biomarkers identified require further evaluation in methodologically robust studies to establish potential clinical utility. Future studies should aim to address the common methodological limitations highlighted in this review to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. What does this study add? This review provides a comprehensive catalogue of investigated biomarkers of systemic treatment response in psoriasis. A diverse range of biomarker types and outcomes was found in the included studies, serving as a key resource for the translational research community.
Asunto(s)
Productos Biológicos , Psoriasis , Productos Biológicos/uso terapéutico , Biomarcadores , Proteínas Adaptadoras de Señalización CARD , Guanilato Ciclasa , Antígenos HLA-C , Humanos , Lipopolisacáridos , Proteínas de la Membrana , FN-kappa B , Proteómica , Psoriasis/terapia , Inhibidores del Factor de Necrosis Tumoral , Ustekinumab/uso terapéuticoRESUMEN
BACKGROUND: Identification of those at risk of more severe psoriasis and/or associated morbidities offers opportunity for early intervention, reduced disease burden and more cost-effective healthcare. Prognostic biomarkers of disease progression have thus been the focus of intense research, but none are part of routine practice. OBJECTIVES: To identify and catalogue candidate biomarkers of disease progression in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with disease progression. The main outcomes were any measure of skin severity or any prespecified psoriasis comorbidity. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (longitudinal design and/or use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise, and mapped to relevant cellular and molecular pathways. RESULTS: Of 181 included studies, most investigated genomic or proteomic biomarkers associated with disease severity (n = 145) or psoriatic arthritis (n = 30). Methodological and reporting limitations compromised interpretation of findings, most notably a lack of longitudinal studies, and inadequate control for key prognostic factors. The following candidate biomarkers with future potential utility were identified for predicting disease severity: LCE3D, interleukin (IL)23R, IL23A, NFKBIL1 loci, HLA-C*06:02 (genomic), IL-17A, IgG aHDL, GlycA, I-FABP and kallikrein 8 (proteomic), tyramine (metabolomic); psoriatic arthritis: HLA-C*06:02, HLA-B*27, HLA-B*38, HLA-B*08, and variation at the IL23R and IL13 loci (genomic); IL-17A, CXCL10, Mac-2 binding protein, integrin b5, matrix metalloproteinase-3 and macrophage-colony stimulating factor (proteomic) and tyramine and mucic acid (metabolomic); and type 2 diabetes mellitus: variation in IL12B and IL23R loci (genomic). No biomarkers were supported by sufficient evidence for clinical use without further validation. CONCLUSIONS: This review provides a comprehensive catalogue of investigated biomarkers of disease progression in psoriasis. Future studies must address the common methodological limitations identified herein to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? The current treatment paradigm in psoriasis is reactive. There is a need to develop effective risk-stratified management approaches that can proactively attenuate the substantial burden of disease. Prognostic biomarkers of disease progression have therefore been the focus of intense research. What does this study add? This review is the first to scope, collate and catalogue research investigating biomarkers of disease progression in psoriasis. The review identifies potentially promising candidate biomarkers for further investigation and highlights common important limitations that should be considered when designing and conducting future studies in this area.
Asunto(s)
Artritis Psoriásica , Diabetes Mellitus Tipo 2 , Psoriasis , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/genética , Biomarcadores/metabolismo , Factores Estimulantes de Colonias , Progresión de la Enfermedad , Antígenos HLA-C/genética , Humanos , Inmunoglobulina G , Integrinas , Interleucina-13 , Interleucina-17 , Interleucinas , Calicreínas , Proteómica , Psoriasis/genética , TiraminaRESUMEN
BACKGROUND: The risk of serious infectious events (SIEs) is increased in patients with rheumatoid arthritis (RA). The aim of this study was to develop an age-adjusted comorbidity index (AACI) to predict, using baseline characteristics, the SIE risk in patients with RA treated with certolizumab pegol (CZP). METHODS: Data of CZP-treated patients with RA were pooled from the RAPID1/RAPID2 randomized controlled trials (RCT CZP) and their open-label extensions (All CZP). Predictors of the first SIE were examined using multivariate Cox models. The AACI was developed by assigning specific weights to patient age and comorbidities on the basis of relative SIE risk. SIE rates were predicted using AACI score and baseline glucocorticoid use, and they were compared with observed rates. The percentage of patients in each SIE risk group achieving low disease activity (LDA)/remission was examined at 1 year of treatment. RESULTS: Among 1224 RCT CZP patients, 40 reported ≥ 1 SIE (incidence rate [IR] 5.09/100 patient-years [PY]), and 201 of 1506 All CZP patients reported ≥ 1 SIE (IR 3.66/100 PY). Age ≥ 70 years, diabetes mellitus, and chronic obstructive pulmonary disease/asthma made the greatest contributions to AACI score. SIE rates predicted using AACI and glucocorticoid use at baseline showed good agreement with observed SIE rates across low-risk and high-risk groups. At 1 year, more high-risk All CZP patients than low-risk All CZP patients reported SIEs (IR 8.4/100 PY vs. IR 3.4/100 PY). Rates of LDA/remission were similar between groups. CONCLUSIONS: AACI and glucocorticoid use were strong baseline predictors of SIE risk in CZP-treated patients with RA. Predicted SIE risk was not associated with patients' likelihood of clinical response. This SIE risk score may provide a valuable tool for clinicians when considering the risk of infection in individual patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00152386 (registered 7 September 2005); NCT00160602 (registered 8 September 2005); NCT00175877 (registered 9 September 2005); and NCT00160641 (registered 8 September 2005).
Asunto(s)
Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Certolizumab Pegol/efectos adversos , Infecciones/epidemiología , Infecciones/etiología , Adulto , Artritis Reumatoide/complicaciones , Comorbilidad , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
BACKGROUND: Comorbidities may contribute to disease activity and treatment response in rheumatoid arthritis (RA) patients. We defined a somatization comorbidity phenotype (SCP) and examined its influence on response to certolizumab pegol (CZP) using data from the PREDICT trial. METHODS: Patients in PREDICT were randomized to the patient-reported Routine Assessment of Patient Index Data 3 (RAPID3) or physician-based Clinical Disease Activity Index (CDAI) for treatment response assessment. Post-hoc analyses identified patients with the SCP, which included diagnosis of depression, fibromyalgia/myalgias, and/or use of medications indicated for treatment of depression, anxiety, or neuropathic pain. The effect of the SCP on RAPID3 or CDAI response at week 12 and low disease activity (LDA; Disease Activity Score in 28 joints based on erythrocyte sedimentation rate ≤ 3.2) at week 52, in week-12 responders, was analyzed using non-parametric analysis of covariance (ANCOVA). RESULTS: At baseline, 43% (313/733) of patients met the SCP classification. Patients with the SCP were 9% more likely to withdraw from the trial. American College of Rheumatology 20% (ACR20), ACR50, and ACR70 responses were 5-14% lower among those with the SCP, and 11% more patients reported adverse events (AEs). Patients without SCP in the CDAI arm were twice as likely to achieve LDA at week 52 compared with those with SCP (32% versus 16%). No differentiation by SCP was observed in the RAPID3 arm (pooled result 21.5%). CONCLUSIONS: We operationalized a potentially important somatization comorbidity phenotype in a trial setting that was associated with a substantially lower likelihood of treatment response and a higher frequency of AEs. Including large numbers of patients with this phenotype in RA trials may reduce the measured clinical effectiveness of a new molecule. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01255761 . Registered on 6 December 2010.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Certolizumab Pegol/uso terapéutico , Adulto , Anciano , Artritis Reumatoide/epidemiología , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Resultado del TratamientoRESUMEN
DNA methylation and histone modifications are key epigenetic regulators of gene expression, and tight connections are known between the two. DNA methyltransferases are upregulated in several tumors and aberrant DNA methylation profiles are a cancer hallmark. On the other hand, histone demethylases are upregulated in cancer cells. Previous work on ES cells has shown that the lysine demethylase KDM1A binds to DNMT1, thereby affecting DNA methylation. In cancer cells, the occurrence of this interaction has not been explored. Here we demonstrate in several tumor cell lines an interaction between KDM1A and both DNMT1 and DNMT3B. Intriguingly and in contrast to what is observed in ES cells, KDM1A depletion in cancer cells was found not to trigger any reduction in the DNMT1 or DNMT3B protein level or any change in DNA methylation. In the S-phase, furthermore, KDM1A and DNMT1 were found, to co-localize within the heterochromatin. Using P-LISA, we revealed substantially increased binding of KDM1A to DNMT1 during the S-phase. Together, our findings propose a mechanistic link between KDM1A and DNA methyltransferases in cancer cells and suggest that the KDM1A/DNMT1 interaction may play a role during replication. Our work also strengthens the idea that DNMTs can exert functions unrelated to act on DNA methylation.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Histona Demetilasas/metabolismo , Neoplasias/metabolismo , Puntos de Control de la Fase S del Ciclo Celular , Animales , Carcinogénesis , Metilación de ADN , Células HeLa , Histona Demetilasas/genética , Histonas/metabolismo , Humanos , Lisina , Ratones , Células 3T3 NIH , Unión Proteica , ADN Metiltransferasa 3BRESUMEN
In addition to genetic predisposition, environmental and lifestyle factors contribute to the pathogenesis of type 2 diabetes (T2D). Epigenetic changes may provide the link for translating environmental exposures into pathological mechanisms. In this study, we performed the first comprehensive DNA methylation profiling in pancreatic islets from T2D and non-diabetic donors. We uncovered 276 CpG loci affiliated to promoters of 254 genes displaying significant differential DNA methylation in diabetic islets. These methylation changes were not present in blood cells from T2D individuals nor were they experimentally induced in non-diabetic islets by exposure to high glucose. For a subgroup of the differentially methylated genes, concordant transcriptional changes were present. Functional annotation of the aberrantly methylated genes and RNAi experiments highlighted pathways implicated in ß-cell survival and function; some are implicated in cellular dysfunction while others facilitate adaptation to stressors. Together, our findings offer new insights into the intricate mechanisms of T2D pathogenesis, underscore the important involvement of epigenetic dysregulation in diabetic islets and may advance our understanding of T2D aetiology.
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Metilación de ADN , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Islotes Pancreáticos/metabolismo , Anciano , Animales , Línea Celular , Islas de CpG , Dermatoglifia del ADN/métodos , Epigénesis Genética , Sitios Genéticos , Glucosa/metabolismo , Humanos , Regiones Promotoras Genéticas , Ratas , Transcripción GenéticaRESUMEN
DNA methyltransferases (DNMTs) establish and maintain DNA methylation patterns at specific regions of the genome, thereby contributing to gene regulation. It is becoming evident that an intricate web of pathways target DNMTs to these genomic regions. Here, we review the understanding of these regulatory mechanisms and provide an overview of the new findings, emphasizing the emerging scenario in which several levels of regulation are coordinated to control DNMTs. The mechanisms involved include the dynamic interplay between interdependent post-translational modifications that regulate DNMTs, post-transcriptional regulation by miRNAs and the emerging role of non-coding RNA in targeting mammalian DNMTs. The analysis of these mechanisms is imperative to the understanding of the role of DNA methylation in regulating gene expression during development and in disease.
Asunto(s)
Metilasas de Modificación del ADN/metabolismo , Regulación Enzimológica de la Expresión Génica , Mamíferos/metabolismo , Animales , Metilación de ADN , Humanos , Mamíferos/genética , MicroARNs/genética , MicroARNs/metabolismo , Procesamiento Proteico-Postraduccional , Interferencia de ARNRESUMEN
DNA methylation was the first epigenetic modification discovered. Until recently, comprehensive coverage of the composition and distribution of methylated cytosines across the genome was lacking. Technological advances, however, are providing methylation maps that can reveal the genomic distribution of DNA methylation in different cell states or phenotypes. The emerging picture includes extensive gene body methylation that is highly conserved in eukaryotes, the presence of DNA methylation in previously unappreciated sequence contexts, and the discovery of another modified DNA base, 5-hydroxymethylcytosine. These new data point to the role of DNA methylation both in gene silencing and gene activation; reconciliation of these seemingly contradictory roles will be essential to fully unravel the biological function of DNA methylation in eukaryotes. Here we review how these recently exposed features of the DNA methylome are challenging previously held dogmas in the field.
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Metilación de ADN , ADN/metabolismo , Genoma , Animales , Islas de CpG , ADN/genética , Silenciador del Gen , Humanos , Leucocitos/citología , Leucocitos/metabolismoRESUMEN
Numerous clinical, physiopathological and epidemiological studies have underlined the detrimental or beneficial role of nutritional factors in complex inflammation related disorders such as allergy, asthma, obesity, type 2 diabetes, cardiovascular disease, rheumatoid arthritis and cancer. Today, nutritional research has shifted from alleviating nutrient deficiencies to chronic disease prevention. It is known that lifestyle, environmental conditions and nutritional compounds influence gene expression. Gene expression states are set by transcriptional activators and repressors and are often locked in by cell-heritable chromatin states. Only recently, it has been observed that the environmental conditions and daily diet can affect transgenerational gene expression via "reversible" heritable epigenetic mechanisms. Epigenetic changes in DNA methylation patterns at CpG sites (epimutations) or corrupt chromatin states of key inflammatory genes and noncoding RNAs, recently emerged as major governing factors in cancer, chronic inflammatory and metabolic disorders. Reciprocally, inflammation, metabolic stress and diet composition can also change activities of the epigenetic machinery and indirectly or directly change chromatin marks. This has recently launched re-exploration of anti-inflammatory bioactive food components for characterization of their effects on epigenome modifying enzymatic activities (acetylation, methylation, phosphorylation, ribosylation, oxidation, ubiquitination, sumoylation). This may allow to improve healthy aging by reversing disease prone epimutations involved in chronic inflammatory and metabolic disorders.
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Dieta , Epigénesis Genética , Alimentos , Inflamación/prevención & control , Enfermedades Metabólicas/prevención & control , Neoplasias/prevención & control , Animales , Cromatina/genética , Enfermedad Crónica , Islas de CpG , Metilación de ADN , Femenino , Humanos , Inflamación/genética , Inflamación/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/inmunología , Enfermedades Metabólicas/metabolismo , Mutación , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismoRESUMEN
Interleukin-6 (IL-6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, metastasis, and subversion of immunity, and changes the response to hormones and to chemotherapeutics. We explored transcription mechanisms involved in differential IL-6 gene expression in breast cancer cells with different metastatic properties. In weakly metastatic MCF7 cells, histone H3 K9 methylation, HP1 binding, and weak recruitment of AP-1 Fra-1/c-Jun, NF-kappaB p65 transcription factors, and coactivators is indicative of low chromatin accessibility and gene transcription at the IL-6 gene promoter. In highly metastatic MDA-MB231 cells, strong DNase, MNase, and restriction enzyme accessibility, as well potent constitutive transcription of the IL-6 gene promoter, coincide with increased H3 S10 K14 phosphoacetylation and promoter enrichment of AP-1 Fra-1/c-Jun and NF-kappaB p65 transcription factors and MSK1, CBP/p300, Brg1, and Ezh2 cofactors. Complementation, silencing, and kinase inhibitor experiments further demonstrate involvement of AP-1 Fra-1/c-Jun and NF-kappaB p65/RelB members, but not of the alpha estrogen receptor in promoting chromatin accessibility and transcription across the IL-6 gene promoter in metastatic breast cancer cells. Finally, the natural withanolide Withaferin A was found to repress IL-6 gene transcription in metastatic breast cancer cells upon dual inhibition of NF-kappaB and AP-1 Fra-1 transcription factors and silencing of IL-6 promoter chromatin accessibility.
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Neoplasias de la Mama/genética , Cromatina/metabolismo , Regulación Neoplásica de la Expresión Génica , Interleucina-6/genética , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción ReIA/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Ergosterol/análogos & derivados , Ergosterol/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histonas/metabolismo , Humanos , Metástasis de la Neoplasia , Regiones Promotoras Genéticas/fisiología , Proteínas Proto-Oncogénicas c-fos/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Interferente Pequeño/metabolismo , Factor de Transcripción AP-1/antagonistas & inhibidores , Factor de Transcripción ReIA/antagonistas & inhibidores , WitanólidosRESUMEN
Controlled expression of cytokine genes is an essential component of an immune response and is crucial for homeostasis. In order to generate an appropriate response to an infectious condition, the type of cytokine, as well as the cell type, dose range and the kinetics of its expression are of critical importance. The nuclear factor-kappaB (NF-kappaB) family of transcription factors has a crucial role in rapid responses to stress and pathogens (innate immunity), as well as in development and differentiation of immune cells (acquired immunity). Although quite a number of genes contain NF-kappaB-responsive elements in their regulatory regions, their expression pattern can significantly vary from both a kinetic and quantitative point of view, reflecting the impact of environmental and differentiative cues. At the transcription level, selectivity is conferred by the expression of specific NF-kappaB subunits and their respective posttranslational modifications, and by combinatorial interactions between NF-kappaB and other transcription factors and coactivators, that form specific enhanceosome complexes in association with particular promoters. These enhanceosome complexes represent another level of signaling integration, whereby the activities of multiple upstream pathways converge to impress a distinct pattern of gene expression upon the NF-kappaB-dependent transcriptional network. Today, several pieces of evidence suggest that the chromatin structure and epigenetic settings are the ultimate integration sites of both environmental and differentiative inputs, determining proper expression of each NF-kappaB-dependent gene. We will therefore discuss in this review the multilayered interplay of NF-kappaB signaling and epigenome dynamics, in achieving appropriate gene expression responses and transcriptional activity.
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Inmunidad Innata/genética , Inflamación/genética , FN-kappa B/fisiología , Animales , Cromatina/fisiología , Epigénesis Genética , Predicción , Regulación de la Expresión Génica/fisiología , Humanos , Quinasa I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Inmunidad Innata/fisiología , Inmunoglobulinas/metabolismo , Factores de Transcripción NFI/metabolismoRESUMEN
We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-kappaB (NF-kappaB)-driven interleukin-6 (IL6) expression. In addition to its physiologic immune function as an acute stress cytokine, sustained elevated expression levels of IL6 promote chronic inflammatory disorders, aging frailty, and tumorigenesis. Our results in estrogen-unresponsive fibroblasts, mitogen- and stress-activated protein kinase (MSK) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that phytoestrogenic isoflavones can selectively block nuclear NF-kappaB transactivation of specific target genes (in particular IL6), independently of their estrogenic activity. This occurs via attenuation of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activity, which further down-regulates MSK-dependent NF-kappaB p65 and histone H3 phosphorylation. As constitutive NF-kappaB and MSK activity are hallmarks of aggressive metastatic ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy.
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Receptor alfa de Estrógeno/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Isoflavonas/farmacología , FN-kappa B/biosíntesis , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Animales , Cromatina/genética , Cromatina/metabolismo , Estradiol/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/fisiología , Regulación de la Expresión Génica/fisiología , Genes Reporteros , Genisteína/farmacología , Histona Acetiltransferasas/metabolismo , Histona Desacetilasas/metabolismo , Humanos , Interleucina-6/biosíntesis , Interleucina-6/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Factor de Transcripción ReIA/biosíntesis , Factor de Transcripción ReIA/genética , Activación Transcripcional/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Apoptotic cells are cleared by phagocytosis during development, homeostasis, and pathology. However, it is still unclear how necrotic cells are removed. We compared the phagocytic uptake by macrophages of variants of L929sA murine fibrosarcoma cells induced to die by tumor necrosis factor-induced necrosis or by Fas-mediated apoptosis. We show that apoptotic and necrotic cells are recognized and phagocytosed by macrophages, whereas living cells are not. In both cases, phagocytosis occurred through a phosphatidylserine-dependent mechanism, suggesting that externalization of phosphatidylserine is a general trigger for clearance by macrophages. However, uptake of apoptotic cells was more efficient both quantitatively and kinetically than phagocytosis of necrotic cells. Electron microscopy showed clear morphological differences in the mechanisms used by macrophages to engulf necrotic and apoptotic cells. Apoptotic cells were taken up as condensed membrane-bound particles of various sizes rather than as whole cells, whereas necrotic cells were internalized only as small cellular particles after loss of membrane integrity. Uptake of neither apoptotic nor necrotic L929 cells by macrophages modulated the expression of proinflammatory cytokines by the phagocytes.