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1.
Int Immunol ; 2020 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-31930291

RESUMEN

Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1 enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.

2.
Arthritis Rheumatol ; 2019 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-31785076

RESUMEN

OBJECTIVE: We previously reported that the co-activation of NF-κB and STAT3 in non-immune cells including synovial fibroblasts enhances the expression of NF-κB target genes, playing a role in chronic inflammation including rheumatoid arthritis (RA). Here we examined the role of NF-κB activation in chondrocytes to understand the pathogenesis of RA. Furthermore, we investigated TMEM147 as a representative NF-κB activator in chondrocytes. METHODS: Clinical samples from RA patients were analyzed by immunohistochemistry. Samples from polydactyly patients served as a control. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several mouse RA models. In vitro experiments including qPCR, RNA interference, immunoprecipitation and confocal microscopy were performed to investigate the mechanism of action of TMEM147 in chondrocytes. RESULTS: Samples from RA patients and from the RA models showed co-activation of NF-κB and STAT3 in chondrocytes (p<0.001). This co-activation induced a synergistic expression of NF-κB targets in vitro (p<0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (p<0.01). TMEM147 was highly expressed in chondrocytes from RA patients and the RA models. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-κB in vitro (p<0.01) and suppressed the cytokine-induced RA in vivo (p<0.01). Mechanistically, TMEM147 molecules acted as a scaffold protein for a NF-κB complex that included breakpoint cluster region and casein kinase 2 to enhance NF-κB activity. CONCLUSION: These results suggest that chondrocytes play a role in the development of RA via TMEM147-mediated NF-κB activation and provide a novel therapeutic strategy for RA.

3.
Int Immunol ; 2019 Dec 25.
Artículo en Inglés | MEDLINE | ID: mdl-31875424

RESUMEN

The immune and nervous systems share many features, including receptor and ligand expression, enabling efficient communication between the two. Accumulating evidence suggests that the communication is bidirectional, with the neural system regulating immune cell functions and vice versa. Steroid hormones from the hypothalamus-pituitary-adrenal gland axis are examples of systemic regulators for this communication. Neural reflexes describe regional regulation mechanisms that are a historically new concept that helps to explain how the neural and body systems including immune system communicate. Several recently identified neural reflexes, including the inflammatory reflex and gateway reflex, significantly impact the activation status of the immune system and are associated with inflammatory diseases and disorders. Either pro-inflammatory or anti-inflammatory effects can be elicited by these neural reflexes. On the other hand, the activities of immune cells during inflammation, for example the secretion of inflammatory mediators, can affect the functions of neuronal systems via neural reflexes and modulate biological outputs via specific neural pathways. In this review article, we discuss recent advances in the understanding of bidirectional neuro-immune interactions, with a particular focus on neural reflexes.

4.
J Cardiovasc Electrophysiol ; 30(12): 2823-2833, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31701593

RESUMEN

BACKGROUND: Activated clotting time (ACT)-guided heparinization is used during atrial fibrillation (AF) ablation. Differences in sensitivity to ACT assays have been identified among different direct oral anticoagulants (DOACs). OBJECTIVE: We aimed to examine ACT just before ablation (pre-ACT) for different ablation start times (9:00, 11:00, 13:00, or 15:00) and ablation safety outcomes in minimally interrupted (min-Int) and uninterrupted (Unint) DOAC regimens and examine differences in pre-ACT values among four DOACs. METHODS: Consecutive patients were randomized into the min-Int (n = 307) or Unint (n = 277) groups. DOACs examined were apixaban, dabigatran, edoxaban, and rivaroxaban. RESULTS: No sequential changes in pre-ACT values were observed for each DOAC used and for all four DOACs combined in the min-Int and Unint groups. There was no meaningful difference in pre-ACT at each ablation start time between the groups. Clinically significant differences in overall pre-ACT were not obtained between the groups (138 ± 24 vs 142 ± 23 seconds). The pre-ACT (baseline) value for dabigatran was on average 29 seconds higher than that for the other three DOACs. The min-Int and Unint groups showed similar thromboembolic (0% vs 0%) and bleeding event rates (major, 1% vs 0%; all, 3.5% vs 2.5%). CONCLUSION: The pre-ACT did not show a sequential change in the min-Int and Unint groups. No notable differences in the time-dependent change in pre-ACT between the groups were observed. Variations in baseline ACT suggest the need for moderate adjustment of ACT for adequate modification of heparin dose for the other three DOACs. Both regimens provided similar acceptable AF ablation safety outcomes.

5.
J Cardiovasc Pharmacol ; 74(3): 246-254, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31498193

RESUMEN

This study aimed to investigate the effects of anticoagulants on ultra-aged patients with nonvalvular atrial fibrillation (AF). We retrospectively studied 320 consecutive patients with AF (median age, 91 years; range 90-100.1 years). Patients were categorized as follows: patients taking direct oral anticoagulant (DOAC group, n = 93), those taking warfarin (warfarin group, n = 147), and those not taking oral anticoagulants (non-OAC group, n = 80). During the follow-up periods (median 3.00 years; first and fourth quantiles, 1.13 and 4.56 years, respectively), in thromboembolic events, the DOAC, warfarin, and non-OAC groups showed the lowest (0%, 0/93; 0%/year), intermediate (4.7%, 7/149; 1.43%/year), and highest (5%, 4/80; 2.65%/year) incidence rates, respectively. In major bleeding events, the DOAC, warfarin, and non-OAC groups showed the highest (9.67%, 9/96; 5.00%/year), intermediate (8.1%, 12/149; 2.46%/year), and lowest (0%, 0/80; 0%/year) incidence rates, respectively. These differences in the relationships of the 3 groups were statistically significant. Confounding factors did not affect these results. Bruises associated with impairment of motor function with aging caused major bleeding in approximately 60% of major bleeding cases. The Cox proportional hazards model revealed that warfarin decreased mortality, whereas antiplatelet drugs increased mortality. In conclusion, DOACs had considerably high incidence of major bleeding events, whereas absence of OAC treatment was associated with substantially high thromboembolic events. Warfarin showed acceptable incidence ratios of both events. At present, warfarin is thus believed to be adequate for ultra-aged (≥90 years) patients with nonvalvular AF. Avoidance of bruises was important to prevent major bleeding events. Antiplatelet drugs were suggested not to be adequate for these patients.

6.
Proc Natl Acad Sci U S A ; 116(35): 17450-17459, 2019 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-31399545

RESUMEN

Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5'-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5'-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor ß (PDGFRß) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, eIF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among eIF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands.

7.
Sci Rep ; 9(1): 10842, 2019 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-31346193

RESUMEN

Zinc (Zn) is an essential nutrient and its deficiency causes immunodeficiency and skin disorders. Various cells including mast cells release Zn-containing granules when activated; however, the biological role of the released Zn is currently unclear. Here we report our findings that Zn transporter ZnT2 is required for the release of Zn from mast cells. In addition, we found that Zn and mast cells induce IL-6 production from inflammatory cells such as skin fibroblasts and promote wound healing, a process that involves inflammation. Zn induces the production of a variety of pro-inflammatory cytokines including IL-6 through signaling pathways mediated by the Zn receptor GPR39. Consistent with these findings, wound healing was impaired in mice lacking IL-6 or GPR39. Thus, our results show that Zn and mast cells play a critical role in wound healing through activation of the GPR39/IL-6 signaling axis.

8.
J Exp Med ; 216(6): 1431-1449, 2019 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-31072819

RESUMEN

Regnase-1 (also known as Zc3h12a or MCPIP-1) is an endoribonuclease involved in mRNA degradation of inflammation-associated genes. Regnase-1 is inactivated in response to external stimuli through post-translational modifications including phosphorylation, yet the precise role of phosphorylation remains unknown. Here, we demonstrate that interleukin (IL)-17 induces phosphorylation of Regnase-1 in an Act1-TBK1/IKKi-dependent manner, especially in nonhematopoietic cells. Phosphorylated Regnase-1 is released from the endoplasmic reticulum (ER) into the cytosol, thereby losing its mRNA degradation function, which leads to expression of IL-17 target genes. By using CRISPR/Cas-9 technology, we generated Regnase-1 mutant mice, in which IL-17-induced Regnase-1 phosphorylation is completely blocked. Mutant mice (Regnase-1AA/AA and Regnase-1ΔCTD/ΔCTD ) were resistant to the IL-17-mediated inflammation caused by T helper 17 (Th17) cells in vivo. Thus, Regnase-1 plays a critical role in the development of IL-17-mediated inflammatory diseases via the Act1-TBK1-IKKi axis, and blockade of Regnase-1 phosphorylation sites may be promising for treatment of Th17-associated diseases.

9.
Immunity ; 50(4): 812-831, 2019 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-30995501

RESUMEN

Since the molecular cloning of interleukin-6 (IL-6) in 1986, many other cytokines have been found to share the same signal transducer, gp130, in their receptor complexes. Thus, the IL-6 family of cytokines now consists of ten members. Although some of the family members' functions are redundant as a result of the expression of gp130, there are also functional distinctions between members. The mechanisms that determine functional redundancies and distinctions are not completely understood. Yet, research has clarified the role of IL-6 family cytokines in autoimmune diseases and has led to effective therapies that target them. Here, we review the IL-6 family of cytokines in autoimmune diseases, with a particular focus on the prototypical member IL-6, from the viewpoints of their structure, signaling, and biological features and discuss possible mechanisms of their functional pleiotropy.


Asunto(s)
Citocinas/fisiología , Pleiotropía Genética , Familia de Multigenes/fisiología , Animales , Enfermedades Autoinmunes/inmunología , Citocinas/genética , Regulación de la Expresión Génica , Inflamación/inmunología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-6/fisiología , Ratones , Subunidades de Proteína , Receptores de Citocinas/fisiología , Receptores de Interleucina-6/fisiología , Transducción de Señal , Relación Estructura-Actividad
10.
Sci Rep ; 9(1): 2353, 2019 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-30787395

RESUMEN

We have reported the gateway reflex, which describes specific neural activations that regulate immune cell gateways at specific blood vessels in the central nervous system (CNS). Four types of gateway reflexes exist, all of which induce alterations in endothelial cells at specific vessels of the blood-brain barrier followed by inflammation in the CNS in the presence of CNS-autoreactive T cells. Here we report a new gateway reflex that suppresses the development of retinal inflammation by using an autoreactive T cell-mediated ocular inflammation model. Exposure to photopic light down-regulated the adrenoceptor pathway to attenuate ocular inflammation by suppressing breaching of the blood-retina barrier. Mechanistic analysis showed that exposure to photopic light down-regulates the expression of α1A-adrenoceptor (α1AAR) due to high levels of norepinephrine and epinephrine, subsequently suppressing inflammation. Surgical ablation of the superior cervical ganglion (SCG) did not negate the protective effect of photopic light, suggesting the involvement of retinal noradrenergic neurons rather than sympathetic neurons from the SCG. Blockade of α1AAR signaling under mesopic light recapitulated the protective effect of photopic light. Thus, targeting regional adrenoceptor signaling might represent a novel therapeutic strategy for autoimmune diseases including those that affect organs separated by barriers such as the CNS and eyes.

11.
Int J Cardiol Heart Vasc ; 22: 55-60, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30603663

RESUMEN

Background: Remote ischemic preconditioning (RIPC) is promising for preventing periprocedural myocardial damage (pMD) in patients undergoing percutaneous coronary intervention (PCI). However, the impact of RIPC on pMD on smokers is not well elucidated. The aim of this study was to investigate an association between tobacco smoking and RIPC on pMD in patients planning to undergo PCI. Methods: This study used data from a multicenter randomized controlled trial involving patients with stable angina who planned to undergo elective PCI. We analyzed data for 262 patients in the control (n = 133) and upper-limb RIPC (n = 129) groups, including 166 current or former smokers. The major outcome was the pMD incidence following PCI, with pMD defined as an elevated level of highly sensitive cardiac troponin T or a creatine kinase myocardial band 12 or 24 h after PCI. Results: The incidence of pMD was significantly lower in the upper-limb RIPC group than in the control group (28/83 patients [33.8%] vs. 43/83 patients [51.8%], respectively; p = 0.018). In a multiple logistic regression model, tobacco smoking was an independent predictor of interacting with and enhancing the effect of RIPC on reducing the incidence of pMD after PCI (regression coefficient, -0.4 [95% confidence interval, -0.74 to -0.082]; p = 0.015). Conclusions: Tobacco smoking may have a beneficial effect on RIPC against pMD after PCI.

12.
J Vasc Access ; 20(1_suppl): 45-49, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-29554827

RESUMEN

PURPOSE: The population of obese patients is increasing in general and also at hemodialysis initiation. For successful cannulation of arteriovenous fistula, the National Kidney Foundation-Dialysis Outcome Quality Initiative guidelines suggest that the required maturation parameters are at a depth of <6 mm. There are several reports describing two-stage superficialization of arteriovenous fistulas in obese cases. Therefore, we investigated the utility and complications of one-stage superficialization of radio-cephalic fistula. METHODS: From January 2011 to March 2017, we simultaneously performed forearm radio-cephalic fistula creation and superficialization of the cephalic vein for 10 patients having obesity (body mass index > 30 kg/m2) and deep cephalic vein (>6 mm). Initially, an arteriovenous anastomosis was created at an appropriate site. Subsequently, an 8-10 cm longitudinal skin incision was made along the lateral aspect of the forearm cephalic vein. The cephalic vein was identified and exposed. The cephalic vein was repositioned superficially. RESULTS: The mean age of the patients was 53 years (range: 40-72 years) and the mean body mass index was 40.2 kg/m2 (33.1-59.7 kg/m2). The cause of renal failure in eight patients was diabetic nephropathy, and in two patients, it was unknown. After the procedure, vein depth became 3.4 mm (1.9-4.6 mm) from 8.2 mm (6.0-13.4 mm). All patients who initiated dialysis underwent successful two-needle cannulation. Primary patency rate was 71.4% at 12 months (two patients underwent percutaneous transluminal angioplasty) and secondary patency rate was 100%. There was one procedure-related complication and delayed wound healing, which was improved by observation without antibiotics. CONCLUSION: This small series of patients indicates that one-stage superficialization of radio-cephalic fistula is a safe and effective option to start hemodialysis in obese subjects.


Asunto(s)
Derivación Arteriovenosa Quirúrgica/métodos , Antebrazo/irrigación sanguínea , Obesidad/complicaciones , Arteria Radial/cirugía , Diálisis Renal , Insuficiencia Renal/terapia , Venas/cirugía , Adulto , Anciano , Derivación Arteriovenosa Quirúrgica/efectos adversos , Índice de Masa Corporal , Cateterismo , Humanos , Japón , Persona de Mediana Edad , Obesidad/diagnóstico , Arteria Radial/diagnóstico por imagen , Arteria Radial/fisiopatología , Insuficiencia Renal/complicaciones , Insuficiencia Renal/diagnóstico , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción Vascular , Venas/diagnóstico por imagen , Venas/fisiopatología
13.
Heart Vessels ; 34(2): 331-342, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30088055

RESUMEN

We evaluated the effects of adjunctive left anterior line (LAL) ablation on LA dyssynchrony and function using real-time three-dimensional echocardiography (3DE) in connection with thromboembolic complications and tachyarrhythmia recurrence in patients with persistent atrial fibrillation (AF). We randomly and prospectively assigned consecutive persistent AF patients to the LAL (n = 52, 65 ± 7 years) and control groups (n = 50, 64 ± 10 years). In the LAL group, extensive encircling pulmonary vein isolation (EEPVI), roof line ablation, and LAL ablation regardless of the extent of the low-voltage area (LVA) were performed. The control group underwent EEPVI and roof line ablation. After ablation, 3DE demonstrated LA dyssynchrony in 23 (46%) and 4 patients (8%, P < 0.001) of the LAL and control groups, respectively. Baseline LA LVAs were relatively small in most patients and there were no significant differences in extent of LVA between control and LAL groups or between patients with and without dyssynchrony. During the follow-up periods (771 ± 121 days), patients with LA dyssynchrony in the LAL group did not show significant differences in symptomatic thromboembolic events (0%) and atrial tachyarrhythmia recurrence (39%) from patients without LA dyssynchrony in the LAL (0% and 30%) and control groups (0% and 32%, respectively). LA ejection fraction and active emptying fraction were lower by 9% on average in the LAL group than in the control group (P < 0.0001). Similarly, in the LAL group, LA ejection fraction, active emptying fraction, and expansion index were significantly lower by approximately 7%, 8%, and 15%, respectively, in LA with dyssynchrony than those in LA without dyssynchrony. In conclusion, LA dyssynchrony and LA hypofunction were induced by LAL ablation in patients with persistent AF and relatively mild LVA. LAL ablation with or without LA dyssynchrony is thought not to affect thromboembolic complications or atrial tachyarrhythmia recurrence.


Asunto(s)
Fibrilación Atrial/cirugía , Función del Atrio Izquierdo/fisiología , Ablación por Catéter/métodos , Atrios Cardíacos/diagnóstico por imagen , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/fisiopatología , Ecocardiografía Tridimensional , Electrocardiografía , Femenino , Estudios de Seguimiento , Atrios Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento
14.
J Invest Dermatol ; 139(2): 333-341, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30273597

RESUMEN

Keloids mark a chronic inflammatory disease characterized by a fibroproliferative disorder of the skin. A genome-wide association study showed that single-nucleotide polymorphism rs8032158 in the neural precursor cell-expressed NEDD4 gene, which has six protein-coding transcript variants (TVs), is genetically linked to keloids. Here, we show that the high frequency of risk allele C in rs8032158 in keloid patients is associated with a selectively higher expression of TV3 of NEDD4 to activate the NF-κB pathway. Comparisons of keloid scars with normal skin samples that do not have the single-nucleotide polymorphism allele and were derived from different anatomical sites showed stronger expressions of NEDD4 TV3 and activated forms of NF-κB and STAT3 in keloid scars. Forced expression or selective knockdown of NEDD4 TV3 increased or decreased NF-κB activation in vitro. Furthermore, NEDD4 knockdown suppressed NF-κB-dependent inflammation development in vivo. Mechanistic analysis showed that NEDD4 TV3 is involved in NF-κB activation through its association with the adaptor protein RIP. These results suggest that NEDD4 TV3 is a potential diagnostic marker and therapeutic target for chronic skin diseases, including keloid.


Asunto(s)
Inflamación/patología , Queloide/patología , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Piel/patología , Adulto , Anciano , Alelos , Biomarcadores/metabolismo , Línea Celular , Niño , Femenino , Fibroblastos , Técnicas de Silenciamiento del Gen , Humanos , Lactante , Inflamación/genética , Queloide/genética , Queratinocitos , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Ubiquitina-Proteína Ligasas Nedd4/genética , Polimorfismo de Nucleótido Simple , Cultivo Primario de Células , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Piel/citología , Adulto Joven
15.
Neurochem Int ; 130: 104303, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-30273641

RESUMEN

Neuroimmunology is a research field that intersects neuroscience and immunology, with the larger aim of gaining significant insights into the pathophysiology of chronic inflammatory diseases such as multiple sclerosis. Conventional studies in this field have so far mainly dealt with immune responses in the nervous system (i.e. neuroinflammation) or systemic immune regulation by the release of glucocorticoids. On the other hand, recently accumulating evidence has indicated bidirectional interactions between specific neural activations and local immune responses. Here we discuss one such local neuroimmune interaction, the gateway reflex. The gateway reflex represents a mechanism that translates specific neural stimulations into local inflammatory outcomes by changing the state of specific blood vessels to allow immune cells to extravasate, thus forming the gateway. Several types of gateway reflex have been identified, and each regulates distinct blood vessels to create gateways for immune cells that induce local inflammation. The gateway reflex represents a novel therapeutic strategy for neuroinflammation and is potentially applicable to other inflammatory diseases in peripheral organs.

16.
J Immunol ; 201(8): 2264-2272, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30209188

RESUMEN

Bmi1 is a polycomb group protein and regulator that stabilizes the ubiquitination complex PRC1 in the nucleus with no evidently direct link to the NF-κB pathway. In this study, we report a novel function of Bmi1: its regulation of IκBα ubiquitination in the cytoplasm. A deficiency of Bmi1 inhibited NF-κB-mediated gene expression in vitro and a NF-κB-mediated mouse model of arthritis in vivo. Mechanistic analysis showed that Bmi1 associated with the SCF ubiquitination complex via its N terminus and with phosphorylation by an IKKα/ß-dependent pathway, leading to the ubiquitination of IκBα. These effects on NF-κB-related inflammation suggest Bmi1 in the SCF complex is a potential therapeutic target for various diseases and disorders, including autoimmune diseases.


Asunto(s)
Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Citoplasma/metabolismo , Células Endoteliales/fisiología , Complejos Multiproteicos/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Complejo Represivo Polycomb 1/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Ligasas SKP Cullina F-box/metabolismo , Animales , Células Cultivadas , Humanos , Ratones , Ratones Endogámicos C57BL , Complejos Multiproteicos/genética , FN-kappa B/metabolismo , Complejo Represivo Polycomb 1/genética , Unión Proteica , Estabilidad Proteica , Proteolisis , Proteínas Proto-Oncogénicas/genética , ARN Interferente Pequeño/genética , Proteínas Ligasas SKP Cullina F-box/genética , Activación Transcripcional , Ubiquitinación
17.
J Immunol ; 201(8): 2256-2263, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30201812

RESUMEN

We recently reported that NF-κB-mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the α subunit of casein kinase II (CK2α) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the γ-secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR-CK2α-p65 complex to induce NF-κB activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-κB p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-κB responsive elements and IL-6 promoter. Furthermore, the transcription of NF-κB target genes was not inhibited by a γ-secretase inhibitor, suggesting that Psen1 regulates NF-κB activation in a manner independent of γ-secretase activity. Mechanistically, Psen1 associated with the BCR-CK2α complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-α-induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR-CK2α-p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR-CK2α-p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Quinasa de la Caseína II/metabolismo , Células Endoteliales/fisiología , FN-kappa B/metabolismo , Presenilina-1/genética , Proteínas Proto-Oncogénicas c-bcr/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Regulación de la Expresión Génica , Humanos , Interleucina-6/genética , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , Presenilina-1/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , Proteínas Proto-Oncogénicas c-bcr/genética , ARN Interferente Pequeño/genética , Factor de Transcripción ReIA/metabolismo , Células Tumorales Cultivadas
18.
Cell Rep ; 24(8): 2196-2210.e9, 2018 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-30134179

RESUMEN

We describe a strategy for developing hydrophilic chemical cocktails for tissue delipidation, decoloring, refractive index (RI) matching, and decalcification, based on comprehensive chemical profiling. More than 1,600 chemicals were screened by a high-throughput evaluation system for each chemical process. The chemical profiling revealed important chemical factors: salt-free amine with high octanol/water partition-coefficient (logP) for delipidation, N-alkylimidazole for decoloring, aromatic amide for RI matching, and protonation of phosphate ion for decalcification. The strategic integration of optimal chemical cocktails provided a series of CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) protocols, which efficiently clear mouse organs, mouse body including bone, and even large primate and human tissues. The updated CUBIC protocols are scalable and reproducible, and they enable three-dimensional imaging of the mammalian body and large primate and human tissues. This strategy represents a future paradigm for the rational design of hydrophilic clearing cocktails that can be used for large tissues.


Asunto(s)
Indicadores y Reactivos/química , Humanos , Interacciones Hidrofóbicas e Hidrofílicas
19.
Glycobiology ; 28(5): 306-317, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29897583

RESUMEN

Membrane-bound sialidases in the mouse thymus are unique and mysterious because their activity at pH 6.5 is equal to or higher than that in the acidic region. The pH curve like this has never been reported in membrane-bound form. To clarify this enzyme, we studied the sialidase activities of crude membrane fractions from immature-T, mature-T and non-T cells from C57BL/6 mice and from SM/J mice, a strain with a defect in NEU1 activity. Non-T cells from C57BL/6 mice had high activity at pH 6.5, but those from SM/J mice did not. Neu1 and Neu3 mRNA was shown by real-time PCR to be expressed in T cells and also in non-T cells, whereas Neu2 was expressed mainly in non-T cells and Neu4 was scarcely expressed. However, the in situ hybridization study on the localization of four sialidases in the thymus showed that Neu4 was clearly expressed. We then focused on a sialidase on the thymocyte surface because the possibility of the existence of a sialidase on thymocytes was suggested by peanut agglutinin (PNA) staining after incubation of the cells alone in PBS. This activity was inhibited by NEU1-selective sialidase inhibitor C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid. The natural substrate for the cell surface sialidase was identified as clustered differentiation 5 (CD5) by PNA-blot analysis of anti-CD5 immunoprecipitate. We conclude that NEU1 exists on the cell surface of mouse thymocytes and CD5 is a natural substrate for it. Although this is not the main reaction of the membrane-bound thymus-sialidases, it must be important for the thymus.


Asunto(s)
Productos Biológicos/metabolismo , Antígenos CD5/metabolismo , Neuraminidasa/metabolismo , Timocitos/metabolismo , Animales , Ratones , Ratones Endogámicos
20.
Neurochem Int ; 118: 176-184, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29920290

RESUMEN

Multiple sclerosis (MS) is an autoimmune disease in which pathogenic T cells play an important role, and an experimental autoimmune encephalomyelitis (EAE) is used as an animal model of MS. Galectins are ß-galactoside-binding lectins and involved in various physiological and pathological events. Among fifteen members of galectins, galectin-1, -8, and -9 play immunosuppressive roles in MS and EAE; however, the role of galectin-3 (gal-3) is complex and controversial. We examined expression of gal-3 in the spinal cord and nerve roots of EAE mice. No immunohistochemical signals were detected in naïve mice, whereas gal-3 appeared at lower lumbar levels of the spinal cord and nerve roots in EAE mice. In the spinal cord, gal-3-positive cells were activated microglia and/or infiltrating macrophages, which were round in shape and intensified for the lysosomal enzyme, cathepsin D, indicating elevated phagocytic activity. Gal-3-positive cells in the spinal cord were most abundant during the peak symptomatic period. In the recovery period, they disappeared from the spinal parenchyma but remained at moderate levels in the pia mater. Interestingly, gal-3-positive cells selectively appeared in ventral, but not dorsal, nerve roots running through the spinal canal, with expression peaking during the recovery period. In ventral nerve roots, the major cell type expressing gal-3 was a specific population of Schwann cells that surround unmyelinated axons and express the biosynthetic enzyme for l-serine, a potent neurotrophic amino acid. Gal-3 was also induced in Iba1/F4/80-positive macrophages, which engulf damaged myelin and axon debris. Thus, gal-3 is induced in distinct cell types that are engaged in removal of damaged axons and cell debris and axon regeneration and remyelination, suggesting a potential neuroprotective role of gal-3 in EAE mice.


Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Galectina 3/biosíntesis , Galectinas/biosíntesis , Microglía/metabolismo , Células de Schwann/metabolismo , Raíces Nerviosas Espinales/metabolismo , Animales , Técnicas de Cocultivo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/patología , Galectina 3/genética , Galectinas/genética , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Células de Schwann/patología , Raíces Nerviosas Espinales/patología
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