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1.
Cancer Res ; 79(19): 4978-4993, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31431460

RESUMEN

Overexpression of the serine/threonine kinase GLK/MAP4K3 in human lung cancer is associated with poor prognosis and recurrence, however, the role of GLK in cancer recurrence remains unclear. Here, we report that transgenic GLK promotes tumor metastasis and cell migration through the scaffold protein IQ motif-containing GTPase-activating protein 1(IQGAP1). GLK transgenic mice displayed enhanced distant metastasis. IQGAP1 was identified as a GLK-interacting protein; two proline-rich regions of GLK and the WW domain of IQGAP1 mediated this interaction. GLK and IQGAP1 colocalized at the leading edge including filopodia and lamellipodia of migrating cells. GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration. GLK-induced cell migration and lung cancer metastasis were abolished by IQGAP1 depletion. Consistently, human NSCLC patient tissues displayed increased phospho-IQGAP1, which correlated with poor survival. Collectively, GLK promotes lung cancer metastasis by binding to, phosphorylating, and activating IQGAP1. SIGNIFICANCE: These findings show the critical role of the GLK-IQGAP cascade in cell migration and tumor metastasis, suggesting it as a potential biomarker and therapeutic target for lung cancer recurrence.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Invasividad Neoplásica/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Activadoras de ras GTPasa/metabolismo , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fosforilación
2.
FASEB J ; : fj201800244RR, 2018 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-29920217

RESUMEN

Dual-specificity phosphatase (DUSP)14 (also known as MAP-kinase phosphatase 6) inhibits T-cell receptor (TCR) signaling and T-cell-mediated immune responses by inactivation of the TGF-ß activated kinase 1 binding protein (TAB1)-TGF-ß activated kinase 1 (TAK1) complex and ERK. DUSP14 phosphatase activity is induced by the E3 ligase TNF receptor associated factor (TRAF)2-mediated Lys63-linked ubiquitination. Here we report an interaction between DUSP14 and protein arginine methyltransferase (PRMT)5 by proximity ligation assay; similarly, DUSP14 directly interacted with TAB1 but not TAK1. DUSP14 is methylated by PRMT5 at arginine 17, 38, and 45 residues. The DUSP14 triple-methylation mutant was impaired in PRMT5-mediated arginine methylation, TRAF2-mediated lysine ubiquitination, and DUSP14 phosphatase activity. Consistently, DUSP14 methylation, TRAF2 binding, and DUSP14 ubiquitination were attenuated by PRMT5 short hairpin RNA knockdown. Furthermore, DUSP14 was inducibly interacted with PRMT5 and was methylated during TCR signaling in T cells. Together, these findings reveal a novel regulatory mechanism of DUSP14 by which PRMT5-mediated arginine methylation may sequentially stimulate TRAF2-mediated DUSP14 ubiquitination and phosphatase activity, leading to inhibition of TCR signaling.-Yang, C.-Y., Chiu, L.-L., Chang, C.-C., Chuang, H.-C., Tan, T.-H. Induction of DUSP14 ubiquitination by PRMT5-mediated arginine methylation.

3.
Cell Signal ; 28(1): 145-51, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26521044

RESUMEN

Dual-specificity phosphatase 14 (DUSP14, also known as MKP6) is a MAP kinase phosphatase that dephosphorylates JNK, ERK, and p38 in vitro. We recently reported that DUSP14 negatively regulates T-cell activation and immune responses by interfering activation of TAB1-TAK1 complex. However, the molecular mechanism that regulates the phosphatase activity of DUSP14 remains unclear. Here, we report the post-translational modification of DUSP14 by ubiquitination. Mass spectrometry and mutational analyses identified that DUSP14 was Lys63-linked ubiquitinated at lysine 103 residue. Furthermore, DUSP14 inducibly interacted with the E3 ligase TRAF2 during T-cell receptor (TCR) signaling; TRAF2 shRNA knockdown reduced the DUSP14 ubiquitination. We also show that ubiquitination of DUSP14 was required for its phosphatase activity during TCR signaling. Together, these findings reveal a novel mechanism by which TRAF2 mediates Lys63-linked ubiquitination of DUSP14, leading to DUSP14 activation in T cells.


Asunto(s)
Fosfatasas de Especificidad Dual/metabolismo , Lisina/metabolismo , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Procesamiento Proteico-Postraduccional/genética , Linfocitos T/inmunología , Factor 2 Asociado a Receptor de TNF/metabolismo , Ubiquitina/metabolismo , Fosfatasas de Especificidad Dual/genética , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Activación de Linfocitos/genética , Quinasas Quinasa Quinasa PAM/metabolismo , FN-kappa B/metabolismo , Fosforilación , Ubiquitinación
4.
Nat Commun ; 5: 4602, 2014 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-25098764

RESUMEN

Proinflammatory cytokines play important roles in insulin resistance. Here we report that mice with a T-cell-specific conditional knockout of HGK (T-HGK cKO) develop systemic inflammation and insulin resistance. This condition is ameliorated by either IL-6 or IL-17 neutralization. HGK directly phosphorylates TRAF2, leading to its lysosomal degradation and subsequent inhibition of IL-6 production. IL-6-overproducing HGK-deficient T cells accumulate in adipose tissue and further differentiate into IL-6/IL-17 double-positive cells. Moreover, CCL20 neutralization or CCR6 deficiency reduces the Th17 population or insulin resistance in T-HGK cKO mice. In addition, leptin receptor deficiency in T cells inhibits Th17 differentiation and improves the insulin sensitivity in T-HGK cKO mice, which suggests that leptin cooperates with IL-6 to promote Th17 differentiation. Thus, HGK deficiency induces TRAF2/IL-6 upregulation, leading to IL-6/leptin-induced Th17 differentiation in adipose tissue and subsequent insulin resistance. These findings provide insight into the reciprocal regulation between the immune system and the metabolism.


Asunto(s)
Resistencia a la Insulina , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Serina-Treonina Quinasas/genética , Factor 2 Asociado a Receptor de TNF/metabolismo , Células Th17/citología , Células 3T3 , Células 3T3-L1 , Tejido Adiposo/metabolismo , Animales , Complejo CD3/metabolismo , Linfocitos T CD4-Positivos/citología , Diferenciación Celular , Exones , Fibroblastos/metabolismo , Prueba de Tolerancia a la Glucosa , Células HEK293 , Humanos , Inflamación , Interleucina-17/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-6/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células Jurkat , Linfocitos/metabolismo , Lisosomas/metabolismo , Ratones , Ratones Noqueados , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Leptina/metabolismo , Transducción de Señal , Quinasa de Factor Nuclear kappa B
5.
J Immunol ; 192(4): 1547-57, 2014 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-24403530

RESUMEN

T cell activation is dependent upon phosphorylation of MAPKs, which play a critical role in the regulation of immune responses. Dual-specificity phosphatase 14 (DUSP14; also known as MKP6) is classified as a MAPK phosphatase. The in vivo functions of DUSP14 remain unclear. Thus, we generated DUSP14-deficient mice and characterized the roles of DUSP14 in T cell activation and immune responses. DUSP14 deficiency in T cells resulted in enhanced T cell proliferation and increased cytokine production upon T cell activation. DUSP14 directly interacted with TGF-ß-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser(438), leading to TAB1-TAK1 complex inactivation in T cells. The phosphorylation levels of the TAB1-TAK1 complex and its downstream molecules, including JNK and IκB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IκB kinase activation in DUSP14-deficient T cells was attenuated by TAB1 short hairpin RNA knockdown. Consistent with that, DUSP14-deficient mice exhibited enhanced immune responses and were more susceptible to experimental autoimmune encephalomyelitis induction. Thus, DUSP14 negatively regulates TCR signaling and immune responses by inhibiting TAB1 activation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Fosfatasas de Especificidad Dual/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Diferenciación Celular/inmunología , Proliferación Celular , Fosfatasas de Especificidad Dual/genética , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Activación Enzimática/inmunología , Humanos , Quinasa I-kappa B/metabolismo , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Interleucina-4/biosíntesis , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Células Jurkat , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Complejos Multiproteicos/metabolismo , Fosforilación , Unión Proteica , Interferencia de ARN , ARN Interferente Pequeño , Células TH1/inmunología , Células Th17/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
6.
J Biol Chem ; 287(41): 34091-100, 2012 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-22902619

RESUMEN

SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) is an adaptor protein that is essential for T cell development and T cell receptor (TCR) signaling activation. Previous studies have identified an important negative feedback regulation of SLP-76 by HPK1 (hematopoietic progenitor kinase 1; MAP4K1)-induced Ser-376 phosphorylation. Ser-376 phosphorylation of SLP-76 mediates 14-3-3 binding, resulting in the attenuation of SLP-76 activation and downstream signaling; however, the underlying mechanism of this action remains unknown. Here, we report that phosphorylated SLP-76 is ubiquitinated and targeted for proteasomal degradation during TCR signaling. SLP-76 ubiquitination is mediated by Ser-376 phosphorylation. Furthermore, Lys-30 is identified as a ubiquitination site of SLP-76. Loss of Lys-30 ubiquitination of SLP-76 results in enhanced anti-CD3 antibody-induced ERK and JNK activation. These results reveal a novel regulation mechanism of SLP-76 by ubiquitination and proteasomal degradation of activated SLP-76, which is mediated by Ser-376 phosphorylation, leading to down-regulation of TCR signaling.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Fosfoproteínas/metabolismo , Proteolisis , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/fisiología , Ubiquitinación/fisiología , Proteínas 14-3-3/genética , Proteínas 14-3-3/inmunología , Proteínas 14-3-3/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Activación Enzimática/fisiología , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Células Jurkat , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/inmunología , MAP Quinasa Quinasa 4/metabolismo , Ratones , Ratones Mutantes , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Fosforilación/fisiología , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Serina/genética , Serina/inmunología , Serina/metabolismo
7.
PLoS One ; 7(4): e34627, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22506037

RESUMEN

BACKGROUND: Pen c 13, identified as a 33-kDa alkaline serine protease, is a major allergen secreted by Penicillium citrinum. Detailed knowledge about the epitopes responsible for IgE binding would help inform the diagnosis/prognosis of fungal allergy and facilitate the rational design of hypoallergenic candidate vaccines. The goal of the present study was to characterize the IgE epitopes of Pen c 13. METHODOLOGY/PRINCIPAL FINDINGS: Serum samples were collected from 10 patients with mold allergy and positive Pen c 13 skin test results. IgE-binding epitopes on rPen c 13 were mapped using an enzymatic digestion and chemical cleavage method, followed by dot-blotting and mass spectrometry. A B-cell epitope-predicting server and molecular modeling were used to predict the residues most likely involved in IgE binding. Theoretically predicted IgE-binding regions were further confirmed by site-directed mutagenesis assays. At least twelve different IgE-binding epitopes located throughout Pen c 13 were identified. Of these, peptides S16 (A(148)-E(166)) and S22 (A(243)-K(274)) were recognized by sera from 90% and 100% of the patients tested, and were further confirmed by inhibition assays. Peptide S22 was selected for further analysis of IgE-binding ability. The results of serum screening showed that the majority of IgE-binding ability resided in the C-terminus. One Pen c 13 mutant, G270A (T(261)-K(274)), exhibited clearly enhanced IgE reactivity, whereas another, K274A, exhibited dramatically reduced IgE reactivity. CONCLUSIONS/SIGNIFICANCE: Experimental analyses confirmed in silico-predicted residues involved in an important antigenic region of Pen c 13. The G270A mutant of Pen c 13 has the potential to serve as an additional tool for the diagnosis/prognosis of mold allergy, and the K274A mutant, as a hypoallergenic form of the epitope, may provide a framework for the design and development of a safe and efficient therapeutic strategy for treating human allergic diseases.


Asunto(s)
Alérgenos/química , Antígenos Fúngicos/química , Proteínas Fúngicas/química , Epítopos Inmunodominantes/química , Inmunoglobulina E/química , Penicillium/inmunología , Alérgenos/inmunología , Alérgenos/metabolismo , Aminoácidos/química , Aminoácidos/metabolismo , Antígenos Fúngicos/inmunología , Antígenos Fúngicos/metabolismo , Sitios de Unión de Anticuerpos , Mapeo Epitopo/métodos , Epítopos de Linfocito B/química , Epítopos de Linfocito B/metabolismo , Proteínas Fúngicas/metabolismo , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Epítopos Inmunodominantes/inmunología , Epítopos Inmunodominantes/metabolismo , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Mutagénesis Sitio-Dirigida/métodos , Penicillium/metabolismo
8.
J Biol Chem ; 287(14): 11037-48, 2012 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-22334673

RESUMEN

Hematopoietic progenitor kinase 1 (HPK1) is a Ste20-like serine/threonine kinase that suppresses immune responses and autoimmunity. B cell receptor (BCR) signaling activates HPK1 by inducing BLNK/HPK1 interaction. Whether HPK1 can reciprocally regulate BLNK during BCR signaling is unknown. Here, we show that HPK1-deficient B cells display hyper-proliferation and hyper-activation of IκB kinase and MAPKs (ERK, p38, and JNK) upon the ligation of BCR. HPK1 attenuates BCR-induced cell activation via inducing BLNK threonine 152 phosphorylation, which mediates BLNK/14-3-3 binding. Furthermore, threonine 152-phosphorylated BLNK is ubiquitinated at lysine residues 37, 38, and 42, leading to attenuation of MAPK and IκB kinase activation in B cells during BCR signaling. These results reveal a novel negative feedback regulation of BCR signaling by HPK1-mediated phosphorylation, ubiquitination, and subsequent degradation of the activated BLNK.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Linfocitos B/metabolismo , Regulación hacia Abajo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Antígenos de Linfocitos B/antagonistas & inhibidores , Transducción de Señal , Ubiquitinación , Proteínas 14-3-3/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Animales , Linfocitos B/citología , Sitios de Unión , Activación Enzimática , Células HEK293 , Humanos , Ratones , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Receptores de Antígenos de Linfocitos B/fisiología
9.
Proteomics Clin Appl ; 2(1): 33-45, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21136777

RESUMEN

The Penicillium genus of fungi is a frequently reported cause of allergic reactions. However, only a limited number of allergens have been reported. In Penicillium spp., many allergens show higher IgE-binding activity in culture filtrate extracts than in cellular extracts. In order to investigate the IgE-reactive profile of mold-sensitized patients, secreted IgE-reactive proteins from Penicillium citrinum were identified by 2-DE, serum immunoblotting, and nanoLC-MS/MS. Among the IgE-reactive spots, one known allergen, Pen c 13, and four novel allergens were identified. The cDNAs coding for Pen c 32 and Pen c 30 were cloned using designed primers based on nanoLC-MS/MS analysis. The amino acid sequences of Pen c 32 and Pen c 30 were, respectively, found to have extensive similarity with those of pectate lyases and catalases from various fungi. Native Pen c 30 was shown to have catalase activity and to bind to serum IgE from 48% of mold-allergic patients and induced immediate type skin reactions in a sensitized patient. Here, we present a proteome approach which resulted in the identification of four novel secreted allergens. These novel allergens might be useful in allergy diagnosis and in the treatment of mold-allergic disorders.

10.
J Immunol ; 178(8): 5237-44, 2007 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-17404307

RESUMEN

Allergenic serine proteases are important in the pathogenesis of asthma. One of these, Pen c 13, is the immunodominant allergen produced by Penicillium citrinum. Many serine proteases induce cytokine expression, but whether Pen c 13 does so in human respiratory epithelial cells is not known. In this study, we investigated whether Pen c 13 caused IL-8 release and activated protease-activated receptors (PARs) in airway epithelial cells. In airway-derived A549 cells and normal human airway epithelial cells, Pen c 13 induced IL-8 release in a dose-dependent manner. Pen c 13 also increased IL-8 release in a time-dependent manner in A549 cells. Pen c 13 cleaved PAR-1 and PAR-2 at their activation sites. Treatment with Pen c 13 induced intracellular Ca(2+) mobilization and desensitized the cells to the action of other proteases and PAR-1 and PAR-2 agonists. Moreover, Pen c 13-mediated IL-8 release was significantly decreased in Ca(2+)-free medium and was abolished by the protease inhibitors, PMSF and 4-(2-aminoethyl) benzenesulfonyl fluoride. Blocking Abs against the cleavage sites of PAR-1 and PAR-2, but not of PAR-4, inhibited Pen c 13-induced IL-8 production, as did inhibition of phospholipase C. Pen c 13 induced IL-8 expression via activation of ERK 1/2, and not of p38 and JNK. In addition, treatment of A549 cells or normal human airway epithelial cells with Pen c 13 increased phosphorylation of ERK 1/2 by a Ca(2+)-dependent pathway. These finding show that Pen c 13 induces IL-8 release in airway epithelial cells and that this is dependent on PAR-1 and PAR-2 activation and intracellular calcium.


Asunto(s)
Alérgenos/farmacología , Interleucina-8/biosíntesis , Pulmón/inmunología , Penicillium/inmunología , Receptor PAR-1/fisiología , Receptor PAR-2/fisiología , Calcio/metabolismo , Células Cultivadas , Células Epiteliales/inmunología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Fosforilación , Inhibidores de Proteasas/farmacología , Fosfolipasas de Tipo C/fisiología
11.
FEBS J ; 272(24): 6218-27, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16336260

RESUMEN

Bermuda grass pollen (BGP) contains a very complex mixture of allergens, but only a few have been characterized. One of the allergens, with an apparent molecular mass of 21 kDa, has been shown to bind serum IgE from 29% of patients with BGP allergy. A combination of chromatographic techniques (ion exchange and reverse phase HPLC) was used to purify the 21 kDa allergen. Immunoblotting was performed to investigate its IgE binding and lectin-binding activities, and the Lysyl-C endopeptidase digested peptides were determined by N-terminal sequencing. The cDNA sequence was analyzed by RACE PCR-based cloning. The protein mass and the putative glycan structure were further elucidated using MALDI-TOF mass spectrometry. The purified 21 kDa allergen was designated Cyn d 24 according to the protocol of International Union of Immunological Societies (IUIS). It has a molecular mass of 18,411 Da by MALDI-TOF analysis and a pI of 5.9. The cDNA encoding Cyn d 24 was predicted to produce a 153 amino acid mature protein containing tow conserved sequences seen in the pathogen-related protein family. Carbohydrate analysis showed that the most abundant N-linked glycan is a alpha(3)-fucosylated pauci-mannose (Man3GlcNAc2) structure, without a Xyl beta-(1,2)-linked to the branching beta-Man. Thus, Cyn d 24 is a glycoprotein and the results of the sequence alignment indicate that this novel allergen is a pathogenesis-related protein 1. To the best of our knowledge, this is the first study to identify any grass pollen allergen as a pathogenesis-related protein 1.


Asunto(s)
Alérgenos/química , Antígenos de Plantas/química , Cynodon/inmunología , Glicoproteínas/química , Proteínas de Plantas/química , Polen/inmunología , Alérgenos/aislamiento & purificación , Secuencia de Aminoácidos , Antígenos de Plantas/aislamiento & purificación , Carbohidratos/análisis , Cromatografía , Glicoproteínas/aislamiento & purificación , Inmunoglobulina E/metabolismo , Lectinas/metabolismo , Datos de Secuencia Molecular , Proteínas de Plantas/aislamiento & purificación , Alineación de Secuencia
12.
J Biomed Sci ; 10(5): 510-7, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12928591

RESUMEN

Accumulative evidence has supported the role of iron in the development of atherosclerosis. To test whether iron-mediated oxidative stress influences plaque stability, apoliporotein-E (ApoE)-deficient mice (3 months old) were placed on a chow diet or a low-iron diet for 3 months, and the abundance of interstitial collagen and the expression of the matrix degradation-associated enzyme, matrix metalloproteinase-9 (MMP-9), in vascular lesions were assessed. A low-iron diet appeared to reduce iron deposition while substantially increasing collagen content of lesions in mice. Immunostaining demonstrated lower expression of MMP-9 in lesions of iron-restricted animals. Likewise, SDS-PAGE zymography revealed lower gelatinolytic activities in aortic tissues and sera of the same group of animals. When older ApoE-deficient mice (5 months old) received a low-iron diet for 2 months, development of the lesion area was not significantly affected. However, the lesional collagen content was much higher in the iron-restricted group of animals, and MMP-9 expression in aortic tissues from the same group of mice was significantly lower. Treatment of murine J774 macrophages with increasing concentrations of ferric ammonium citrate significantly enhanced the amount of MMP-9 secreted. Together, these data indicate that decreased vascular iron content following dietary iron restriction in ApoE-deficient mice leads to lower matrix degradation capacity and increased plaque stability.


Asunto(s)
Apolipoproteínas E/deficiencia , Deficiencias de Hierro , Hierro/farmacología , Animales , Apolipoproteínas E/genética , Arteriosclerosis/patología , Línea Celular , Colágeno/metabolismo , Dieta , Inmunohistoquímica , Hierro/administración & dosificación , Hierro/metabolismo , Macrófagos , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Noqueados
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