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1.
Lupus ; 29(2): 176-181, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31924143

RESUMEN

OBJECTIVE: The objective of this study was to evaluate the chronic damage associated with pregnancies before and after the diagnosis of systemic lupus erythematosus (SLE). METHODS: Using childbearing-aged female SLE patient data registered at the Okayama and Showa University Hospitals, a nested case-control analysis was performed to investigate the relationship between pregnancy and chronic damage using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). RESULTS: Pregnancy occurred in 22 patients before and 13 patients after the diagnosis of SLE in 104 eligible patients. Live births occurred in 82% (33/40) and 50% (9/18) of the pregnancies before and after the diagnosis of SLE, respectively. After matching age and disease duration, 33 case patients with chronic damage (SDI ≥ 1) and 33 control patients without chronic damage (SDI = 0) were selected. Hypertension was more frequent in cases than in controls (48% vs. 24%, p = 0.041). Pregnancies before and after the diagnosis of SLE were comparable between cases and controls (before the diagnosis: nine case patients and eight control patients; after the diagnosis: three case patients and five control patients; p = 1.00). Even after adjusting for hypertension using multivariate analysis, the pregnancies before and after the diagnosis were not significant predictors for chronic damage (odds ratio = 1.48 (95% confidence interval 0.33-6.65)), p = 0.60 of the pregnancy before the diagnosis; odds ratio = 0.78 (95% confidence interval 0.13-4.74), p = 0.78 of the pregnancy after the diagnosis). CONCLUSION: Pregnancies, either before or after the diagnosis of SLE, did not show any differences in chronic damage. Our results help alleviate fears regarding childbearing in female patients with SLE and their families.


Asunto(s)
Estado de Salud , Lupus Eritematoso Sistémico/fisiopatología , Complicaciones del Embarazo , Adulto , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Japón , Modelos Logísticos , Lupus Eritematoso Sistémico/diagnóstico , Análisis Multivariante , Embarazo , Sistema de Registros , Índice de Severidad de la Enfermedad , Adulto Joven
3.
Lupus ; 25(1): 54-60, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26296361

RESUMEN

OBJECTIVE: We have assessed the effectiveness of tacrolimus for minor flares in systemic lupus erythematosus (SLE) patients. METHODS: The medical records of 313 patients were retrospectively reviewed over a period of seven years, from 2006 to 2013. We enrolled patients with minor flare treated with add-on tacrolimus, without glucocorticoid (GC) intensification (tacrolimus group). Minor flare was defined as a ≥ 1-point increase in a total score between 3 and 11 in the SLE Disease Activity Index (SLEDAI). We enrolled as controls patients who were administered increased doses of GC for minor flare (GC group). All patients were followed for one year. The primary outcome measure was the proportion of responders. RESULTS: There were 14 eligible patients in the tacrolimus group and 20 eligible patients in the GC group. The mean SLEDAI at flare tended to be higher in the tacrolimus group than in the GC group (7.5 vs. 6.2, p = 0.085). A mean dose of 1.6 mg tacrolimus/day was administered for flare, while the mean GC dose was 13.7 mg/day in the GC group. The proportion of responders was 86% (12/14) in the tacrolimus group and 75% (15/20) in the GC group (p = 0.67). The mean dose of GC at 12 months was higher in the GC group than in the tacrolimus group (9.7 mg/day vs. 7.1 mg/day, p < 0.05). Only one patient discontinued tacrolimus because of fatigue after three months. CONCLUSION: Adding tacrolimus without increasing the GC dose may provide an effective treatment option for minor flares in patients with SLE.


Asunto(s)
Inmunosupresores/administración & dosificación , Lupus Eritematoso Sistémico/tratamiento farmacológico , Tacrolimus/administración & dosificación , Adulto , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Glucocorticoides/administración & dosificación , Humanos , Inmunosupresores/efectos adversos , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Registros Médicos , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tacrolimus/efectos adversos , Factores de Tiempo , Resultado del Tratamiento
4.
Scand J Rheumatol ; 42(4): 253-9, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23470089

RESUMEN

OBJECTIVES: The retention of the anti-rheumatic agent tocilizumab (TCZ) has not been well documented in patients with rheumatoid arthritis (RA). We conducted an observational study to compare the retention of TCZ and anti-tumour necrosis factor (TNF) drugs in the treatment of patients with RA. METHOD: We reviewed continuation rates and causes of discontinuation of biological agents (biologics) by assessing medical records of patients with RA who were administered biologics at our institute from September 1999 to April 2012, using the Osaka University Biologics for Rheumatic Diseases (BiRD) registry. RESULTS: A total of 401 patients were included. TCZ, infliximab (IFX), etanercept (ETN), and adalimumab (ADA) were administered to 97, 103, 143, and 58 patients, respectively. There were some differences between the baseline characteristics of the groups. The median duration (range) of TCZ, IFX, ETN, and ADA administration was 2.5 (0.1-12.6), 1.9 (0.0-7.7), 2.9 (0.0-11.3), and 1.3 (0.0-3.4) years, respectively. Continuation rates for TCZ and ETN were significantly higher than those for IFX and ADA. Multivariate analyses showed that discontinuation due to lack or loss of efficacy was significantly less common in the TCZ group than in the other groups. Discontinuation due to overall adverse events was not significantly different between treatment groups. CONCLUSION: TCZ and ETN show better retention than IFX or ADA in the treatment of RA.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales/farmacocinética , Artritis Reumatoide/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Artritis Reumatoide/diagnóstico , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Infliximab , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto Joven
5.
J Exp Med ; 193(2): 263-9, 2001 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-11208867

RESUMEN

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1) is known to function as a negative feedback regulator of cytokine signaling, but it is unclear whether it is involved in other biological events. Here, we show that SSI-1 participates and plays an important role in the insulin signal transduction pathway. SSI-1-deficient mice showed a significantly low level of blood sugar. While the forced expression of SSI-1 reduced the phosphorylation level of insulin receptor substrate 1 (IRS-1), SSI-1 deficiency resulted in sustained phosphorylation of IRS-1 in response to insulin.Furthermore, SSI-1 achieves this inhibition both by binding directly to IRS-1 and by suppressing Janus kinases. These findings suggest that SSI-1 acts as a negative feedback factor also in the insulin signal transduction pathway through the suppression of IRS-1 phosphorylation.


Asunto(s)
Proteínas Portadoras/metabolismo , Insulina/metabolismo , Fosfoproteínas/metabolismo , Proteínas Represoras , Animales , Secuencia de Bases , Proteínas Portadoras/genética , Cartilla de ADN/genética , Retroalimentación , Hipoglucemia/genética , Hipoglucemia/metabolismo , Insulina/farmacología , Proteínas Sustrato del Receptor de Insulina , Proteínas Quinasas JNK Activadas por Mitógenos , Ratones , Ratones Noqueados , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Fosforilación , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas
6.
FEBS Lett ; 401(1): 49-52, 1997 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-9003804

RESUMEN

The structure of leptin receptor (OB-R) is highly homologous to that of gp130, the common signal transducing receptor component for the interleukin-6 family of cytokines. Based on this structural similarity, we examined signaling processes initiated by OB-R in comparison with those by gp130. Stimulation of either a long form of OB-R or gp130 led to tyrosine phosphorylation of STAT3, whereas stimulation of the truncated form of OB-R that is predominantly expressed in dbldb mice failed to do so. Stimulation of the long form OB-R did not induce tyrosine phosphorylation of a Src homology domain 2 containing protein tyrosine phosphatase, SHP-2, while stimulation of gp130 did. In contrast, activation of p42ERK2 is mediated by either the long form OB-R or gp130. Two closely related molecules, OB-R and gp130, thus appear to mediate overlapping but distinct signaling procedures.


Asunto(s)
Antígenos CD/metabolismo , Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Superficie Celular , Receptores de Citocinas/metabolismo , Transducción de Señal , Receptor gp130 de Citocinas , Activación Enzimática , Humanos , Fosforilación , Proteínas Quinasas/metabolismo , Receptores de Leptina , Proteínas Recombinantes/metabolismo , Tirosina/metabolismo
7.
FEBS Lett ; 403(1): 79-82, 1997 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-9038364

RESUMEN

Leptin (OB) exerts weight-reducing effects in mice. The structure of the receptor for this factor, OB-R, is considerably similar to those of gp130, the common signal transducing receptor component for the interleukin-6 (IL-6) family of cytokines, and leukemia inhibitory factor receptor (LIFR). Since the IL-6 family of cytokines signal through gp130 homodimer or gp130/LIFR heterodimer, we have examined in this study the possible involvement of gp130 and LIFR in leptin signaling through OB-R. Leptin stimulation induces tyrosine phosphorylation of neither gp130 nor LIFR, while LIF stimulation does both. As examined by using two differently epitope-tagged OB-R molecules, the spontaneous homo-oligomerization of OB-R has been elucidated. Ba/F3 cells, which do not express gp130, are non-responsive to leptin and exhibit increased DNA synthesis in response to leptin after transfection of OB-R cDNA alone. OB-R appears to transduce the signal via its homo-oligomerization without interaction with gp130 or LIFR.


Asunto(s)
Antígenos CD/metabolismo , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Inhibidores de Crecimiento , Interleucina-6 , Linfocinas , Glicoproteínas de Membrana/metabolismo , Receptores de Superficie Celular , Receptores de Citocinas/metabolismo , Animales , Antígenos CD/química , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Western Blotting , Células COS/metabolismo , Proteínas Portadoras/genética , Receptor gp130 de Citocinas , ADN/biosíntesis , ADN/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Epítopos , Interleucina-3/farmacología , Leptina , Factor Inhibidor de Leucemia , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia , Glicoproteínas de Membrana/química , Ratones , Fosforilación , Pruebas de Precipitina , Conformación Proteica , Proteínas/farmacología , Receptores de Leptina , Receptores OSM-LIF , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Factor de Transcripción STAT3 , Transducción de Señal , Transactivadores/metabolismo , Transfección , Tirosina/metabolismo
8.
FEBS Lett ; 401(2-3): 133-7, 1997 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-9013873

RESUMEN

Vav is a hematopoietic cell-specific proto-oncogene. We show that interleukin-6 (IL-6) induces transient tyrosine phosphorylation of Vav in a human myeloma cell line, U266. A membrane-distal part of the cytoplasmic region of gp130 is critical for association between Vav and gp130, and the IL-6-induced tyrosine phosphorylation of Vav. Mitogen-activated protein kinase (MAPK) (p42MAPK or extracellular signal-regulated kinase 2 (Erk2)) is coprecipitated with Vav. MAPK activity in the anti-Vav immunoprecipitates is upregulated by IL-6 stimulation. Furthermore Vav is associated with Grb2 which is known as an adapter protein leading to Ras activation. The results imply that Vav may link gp130 activation to downstream MAPK activation in hematopoietic cells.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Antígenos CD/metabolismo , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas de Ciclo Celular , Interleucina-6/fisiología , Glicoproteínas de Membrana/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Membrana Celular/metabolismo , Receptor gp130 de Citocinas , Proteína Adaptadora GRB2 , Humanos , Proteína Quinasa 1 Activada por Mitógenos , Fosforilación , Pruebas de Precipitina , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-vav , Proteínas Recombinantes/metabolismo , Células Tumorales Cultivadas , Tirosina/metabolismo
10.
Immunol Lett ; 31(2): 123-30, 1992 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-1740350

RESUMEN

IL-6 mediates its pleiotropic functions through two membrane proteins, a ligand-binding molecule (IL-6 receptor, IL-6R) and a non-ligand-binding signal transducer (gp130). Starting with a previously isolated cDNA clone encoding human gp130, recombinant soluble gp130 (sgp130) lacking the transmembrane and cytoplasmic regions was expressed in COS7 cells or CHO cells. sgp130 could associate with a complex of IL-6 and soluble IL-6R (sIL-6R), also lacking transmembrane and cytoplasmic regions. This indicated that extracellular region of gp130 was responsible for the association with IL-6R which was occupied by IL-6. An enzyme-linked immunosorbent assay (ELISA) for the quantitation of sgp130 was established, which was based on the interaction of sgp130 with the complex of IL-6 and sIL-6R and could detect sgp130 as low as 1 ng/ml.


Asunto(s)
Antígenos CD , Interleucina-6/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Secuencia de Bases , Receptor gp130 de Citocinas , ADN/genética , Ensayo de Inmunoadsorción Enzimática/métodos , Humanos , Glicoproteínas de Membrana/análisis , Glicoproteínas de Membrana/genética , Datos de Secuencia Molecular , Receptores de Interleucina-6 , Proteínas Recombinantes/análisis , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal/inmunología , Solubilidad
12.
Blood ; 98(10): 3042-9, 2001 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-11698289

RESUMEN

Receptor usage by viral interleukin-6 (vIL-6), a virokine encoded by Kaposi sarcoma- associated herpesvirus, is an issue of controversy. Recently, the crystal structure of vIL-6 identified vIL-6 sites II and III as directly binding to glycoprotein (gp)130, the common signal transducer for the IL-6 family of cytokines. Site I of vIL-6, however, comprising the outward helical face of vIL-6, where human IL-6 (hIL-6) would interact with the specific alpha-chain IL-6 receptor (IL-6R), is accessible and not occupied by gp130. This study examined whether this unused vIL-6 surface is available for IL-6R binding. By enzyme-linked immunosorbent assay, vIL-6 bound to soluble gp130 (sgp130) but not to soluble IL-6R (sIL-6R). Using plasmon surface resonance, vIL-6 bound to sgp130 with a dissociation constant of 2.5 microM, corresponding to 1000-fold lower affinity than that of hIL-6/sIL-6R complex for gp130. sIL-6R neither bound to vIL-6 nor affected vIL-6 binding to gp130. In bioassays, vIL-6 activity was neutralized by 4 monoclonal antibodies (mAbs) recognizing a domain within vIL-6 site I, mapped to the C-terminal part of the AB-loop and the beginning of helix B. The homologous region in hIL-6 participates in site I binding to IL-6R. In addition, binding of vIL-6 to sgp130 was interfered with specifically by the 4 neutralizing anti-vIL-6 mAbs. Based on the vIL-6 crystal structure, the vIL-6 neutralizing mAbs map outside the binding interface to gp130, suggesting that they either produce allosteric changes or block necessary conformational changes in vIL-6 preceding its binding to gp130. These results document that vIL-6 does not bind IL-6R and suggest that conformational change may be critical to vIL-6 function.


Asunto(s)
Herpesvirus Humano 8/genética , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , Proteínas Virales/metabolismo , Regulación Alostérica , Animales , Anticuerpos Monoclonales/biosíntesis , Anticuerpos Monoclonales/inmunología , Antígenos CD/química , Antígenos CD/metabolismo , Western Blotting , Cristalografía por Rayos X , Receptor gp130 de Citocinas , Epítopos/inmunología , Humanos , Interleucina-6/química , Interleucina-6/genética , Interleucina-6/inmunología , Sustancias Macromoleculares , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/metabolismo , Ratones , Modelos Moleculares , Pruebas de Neutralización , Unión Proteica , Conformación Proteica , Receptores de Interleucina-6/química , Proteínas Recombinantes de Fusión/química , Solubilidad , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie , Proteínas Virales/química , Proteínas Virales/genética , Proteínas Virales/inmunología
13.
Bioconjug Chem ; 12(4): 510-4, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11459454

RESUMEN

Water-soluble gadolinium (Gd) endohedral metallofullerenes have been synthesized as polyhydroxyl forms (Gd@C(82)(OH)(n)(), Gd-fullerenols) and their paramagnetic properties were evaluated by in vivo as well as in vitro for the novel magnetic resonance imaging (MRI) contrast agents for next generation. The in vitro water proton relaxivity, R(1) (the effect on 1/T(1)), of Gd-fullerenols is significantly higher (20-folds) than that of the commercial MRI contrast agent, Magnevist (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA) at 1.0 T close to the common field of clinical MRI. This unusually high proton relaxivity of Gd-fullerenols leads to the highest signal enhancement at extremely lower Gd concentration in MRI studies. The strong signal was confirmed in vivo MRI at lung, liver, spleen, and kidney of CDF1 mice after i.v. administration of Gd-fullerenols at a dose of 5 micromol Gd/kg, which was 1/20 of the typical clinical dose (100 micromol Gd/kg) of Gd-DTPA.


Asunto(s)
Medios de Contraste/síntesis química , Fulerenos , Aumento de la Imagen/métodos , Animales , Carbono/química , Carbono/farmacocinética , Medios de Contraste/química , Medios de Contraste/farmacocinética , Estudios de Evaluación como Asunto , Femenino , Gadolinio/química , Gadolinio/farmacocinética , Gadolinio DTPA/química , Gadolinio DTPA/farmacocinética , Riñón/metabolismo , Riñón/patología , Hígado/metabolismo , Hígado/patología , Pulmón/metabolismo , Pulmón/patología , Imagen por Resonancia Magnética , Ratones , Resonancia Magnética Nuclear Biomolecular , Compuestos Organometálicos/química , Fantasmas de Imagen , Protones , Solubilidad , Bazo/metabolismo , Bazo/patología , Distribución Tisular
14.
Ciba Found Symp ; 167: 5-16; discussion 16-23, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-1425018

RESUMEN

Functional pleiotropy and redundancy are characteristic features of cytokines. Interleukin 6 (IL-6) is a typical example: IL-6 induces cellular differentiation or expression of tissue-specific genes; it is involved in processes such as antibody production in B cells, acute-phase protein synthesis in hepatocytes, megakaryocyte maturation, cytotoxic T cell differentiation, and neural differentiation of PC12 (pheochromocytoma) cells. It promotes growth of myeloma/plasmacytoma cells, T cells, keratinocytes and renal mesangial cells, and it inhibits growth of myeloid leukaemic cell lines and certain carcinoma cell lines. The IL-6 receptor consists of two polypeptide chains, a ligand-binding chain (IL-6R) and a non-ligand-binding, signal-transducing chain (gp130). Interaction of IL-6 with IL-6R triggers the association of gp130 and IL-6R, and the signal can be transduced through gp130. Association of gp130 with IL-6R is involved in the formation of high affinity binding sites. This two-chain model has been shown to be applicable to receptor systems for several other cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-5 and nerve growth factor (NGF). The pleiotropy and redundancy of cytokines may be explained on the basis of this unique receptor system.


Asunto(s)
Interleucina-6/fisiología , Receptores Inmunológicos/fisiología , Animales , Glicoproteínas/fisiología , Humanos , Interleucina-6/química , Receptores Inmunológicos/química , Receptores de Interleucina-6 , Transducción de Señal/fisiología
15.
J Immunol ; 164(11): 5833-43, 2000 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-10820262

RESUMEN

STAT-induced STAT inhibitor-1 (SSI-1), also referred to as suppressor of cytokine signaling-1 and JAK-binding protein, is a member of a new family, the members of which are negative regulators of cytokine signals. SSI-1 is induced by various cytokines; however, the transcriptional mechanism of the SSI-1 gene is not fully understood. Here, we showed that transcription of the mouse SSI-1 gene was initiated from six adjoining sites accompanying three GC boxes and a single GC box-like element near them, but not from the TATA box or an initiator sequence. We also showed that IFN-gamma induced SSI-1 mRNA more strongly than IL-6 in NIH-3T3 fibroblasts and that this IFN-gamma effect was mediated by Stat1. To determine the signal pathway downstream of Stat1, transcriptional activities of several mutant promoters were examined. The region mediating stimulatory effect of IFN-gamma to the gene transcription was localized to the -88/-60 region containing three tandem GAAA units, named variant IFN-gamma-responsive element (VIRE), while four IFN-gamma activation site (GAS)-like elements located far upstream were not related to the IFN-gamma response. Gel-shift assays revealed that IFN-gamma induced IFN regulatory factor-1 (IRF-1) binding to VIRE, but not that of IRF-2 or three components of ISGF3. Furthermore, forced expression of IRF-1 mimicked and that of IRF-2 inhibited the stimulatory effect of IFN-gamma on SSI-1 gene transcription. Finally, mouse embryonal fibroblasts lacking IRF-1 showed impaired SSI-1 mRNA induction by IFN-gamma. These results demonstrated that IRF-1, which is induced by activation of Stat1, mediated transcriptional activation of the SSI-1 gene by IFN-gamma via VIRE.


Asunto(s)
Proteínas Portadoras/genética , Proteínas de Unión al ADN/fisiología , Interferón gamma/fisiología , Fosfoproteínas/fisiología , Regiones Promotoras Genéticas/inmunología , Proteínas Represoras , Transducción de Señal/inmunología , Transactivadores/fisiología , Células 3T3/metabolismo , Animales , Secuencia de Bases , Proteínas Portadoras/biosíntesis , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Citocinas/farmacología , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Sinergismo Farmacológico , Electroforesis en Gel de Poliacrilamida , Fibroblastos/metabolismo , Sustancias de Crecimiento/farmacología , Factor 1 Regulador del Interferón , Ratones , Datos de Secuencia Molecular , Fosfoproteínas/deficiencia , Fosfoproteínas/genética , ARN Mensajero/biosíntesis , Elementos de Respuesta/inmunología , Transducción de Señal/genética , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas , Secuencias Repetidas en Tándem/inmunología , Transcripción Genética/inmunología , Factor de Necrosis Tumoral alfa/fisiología
16.
Eur J Immunol ; 23(5): 1078-82, 1993 May.
Artículo en Inglés | MEDLINE | ID: mdl-8477802

RESUMEN

The characteristics of soluble interleukin-6 receptor (sIL-6R) in murine sera were examined. To investigate a relationship between serum sIL-6R level and autoimmune diseases, quantitative analysis of serum sIL-6R in MRL/lpr mice was performed by an enzyme-linked immunosorbent assay. The serum sIL-6R level in MRL/lpr mice of both sexes was below the detection limit (< 1.0 ng/ml) at 8 weeks of age, but it increased in accordance with age and reached 42 +/- 9.3 ng/ml in female and 31 +/- 13 ng/ml in male mice at 30 weeks of age. In MRL/+ mice, although an age-associated increase in serum sIL-6R level was observed, it was much less extensive than that in MRL/lpr mice. Elevated serum sIL-6R level at the age of 30 weeks was observed in female and male (NZB x NZW)F1 mice (32 +/- 10 ng/ml and 17 +/- 5.0 ng/ml, respectively), and male BXSB/Mpj Yaa mice (42 +/- 18 ng/ml), suggesting that elevated serum sIL-6R in aged mice is one of the characteristics of autoimmune-prone mice. Quantitative analysis of serum IL-6 in MRL/lpr revealed that the serum sIL-6R level correlated well with the serum IL-6 level. We also showed that sIL-6R in the sera from MRL/lpr mice could mediate the IL-6 functions through the IL-6 signal-transducing receptor component gp130, suggesting that elevated production of sIL-6R may partly contribute to development of autoimmune disease in MRL/lpr mice.


Asunto(s)
Envejecimiento/inmunología , Enfermedades Autoinmunes/sangre , Interleucina-6/farmacología , Trastornos Linfoproliferativos/sangre , Receptores Inmunológicos/análisis , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Interleucina-6/sangre , Masculino , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos C57BL , Ratones Endogámicos NZB , Receptores Inmunológicos/fisiología , Receptores de Interleucina-6 , Proteínas Recombinantes/farmacología
17.
Proc Natl Acad Sci U S A ; 88(24): 11349-53, 1991 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-1662392

RESUMEN

Interleukin 6 (IL-6) signal is transduced through gp130 that associates with a complex of IL-6 and IL-6 receptor. Truncations or amino acid substitutions offe introduced in the cytoplasmic region of human gp130, and the mutant cDNAs were transfected into murine interleukin 3-dependent cells to determine amino acid residues critical for generating the IL-6-mediated growth signal. In the 277-amino acid cytoplasmic region of gp130, a 61-amino acid region proximal to the transmembrane domain was sufficient for generating the growth signal. In this region, two short segments were significantly homologous with other cytokine-receptor family members. One segment is conserved in almost all members of the family, and the other is found especially in granulocyte colony-stimulating factor receptor, interleukin 2 receptor beta chain, erythropoietin receptor, KH97 (a granulocyte/macrophage colony-stimulating factor receptor-associated molecule), and interleukin 3 receptor. gp130 molecules with mutations in either of these two segments could not transduce growth signal. Loss of signal-transducing ability of gp130 with such a mutation coincided with disappearance of IL-6-induced tyrosine phosphorylation of gp130.


Asunto(s)
Antígenos CD , Evolución Biológica , Citocinas/inmunología , Interleucina-6/fisiología , Glicoproteínas de Membrana/genética , Receptores de Superficie Celular/inmunología , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Transducción de Señal , Secuencia de Aminoácidos , Animales , Receptor gp130 de Citocinas , Citoplasma/fisiología , Humanos , Cinética , Sustancias Macromoleculares , Glicoproteínas de Membrana/farmacocinética , Datos de Secuencia Molecular , Familia de Multigenes , Mutagénesis Sitio-Dirigida , Plásmidos , Receptores Inmunológicos/fisiología , Receptores de Interleucina-6 , Mapeo Restrictivo , Homología de Secuencia de Ácido Nucleico , Transfección
18.
Proc Natl Acad Sci U S A ; 91(6): 2285-9, 1994 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-8134389

RESUMEN

The interleukin 6 receptor-associated signal transducer, gp130, is shared by receptor complexes for leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and interleukin 11. We show here that JAK2 kinase is rapidly tyrosine phosphorylated in mouse embryonic stem cells whose pluripotentiality is maintained only by gp130-sharing cytokines after stimulation that is known to induce gp130 homodimerization. JAK1 is also tyrosine phosphorylated, but to a lesser extent, under the same conditions. Comparable results are obtained with hemopoietic lineage cells such as myeloid leukemic M1 cells and pro-B-cell line-derived transfectants expressing gp130, the former of which differentiate into macrophages after stimulation of gp130 and the latter of which initiate DNA synthesis. gp130-dimerizing stimulus upregulates kinase activity of JAK2 as revealed by immunocomplex kinase assay. Deletion or point mutation in the membrane-proximal cytoplasmic motifs in gp130 that are conserved in the hemopoietic cytokine receptor family results in the loss of tyrosine phosphorylation of JAK2, which coincides with the lack of signal transducing capability of gp130 mutants.


Asunto(s)
Antígenos CD , Interleucina-6/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas , Animales , Receptor gp130 de Citocinas , Activación Enzimática , Janus Quinasa 2 , Ratones , Células Madre Neoplásicas , Reacción en Cadena de la Polimerasa , Receptores de Interleucina/metabolismo , Receptores de Interleucina-6 , Transducción de Señal
19.
J Immunol ; 165(4): 1799-806, 2000 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-10925257

RESUMEN

Previous experiments have shown that STAT-induced STAT inhibitor-1 (SSI-1; also named suppressors of cytokine signaling-1 (SOCS-1) or Janus kinase binding protein) is predominantly expressed in lymphoid organs and functions in vitro as a negative regulator of cytokine signaling. To determine the function of SOCS-1 in vivo, we generated SSI-1 transgenic mice using the lck proximal promoter that drives transgene expression in T cell lineage. In thymocytes expressing SSI-1 transgene, tyrosine phosphorylation of STATs in response to cytokines such as IFN-gamma, IL-6, and IL-7 was inhibited, suggesting that SSI-1 suppresses cytokine signaling in primary lymphocytes. In addition, lck-SSI-1 transgenic mice showed a reduction in the number of thymocytes as a result of the developmental blocking during triple-negative stage. They also exhibited a relative increase in the percentage of CD4+ T cells, a reduction in the number of gammadelta T cells, as well as the spontaneous activation and increased apoptosis of peripheral T cells. Thus, enforced expression of SSI-1 disturbs the development of thymocytes and the homeostasis of peripheral T cells. All these features of lck-SSI-1 transgenic mice strikingly resemble the phenotype of mice lacking common gamma-chain or Janus kinase-3, suggesting that transgene-derived SSI-1 inhibits the functions of common gamma-chain-using cytokines. Taken together, these results suggest that SSI-1 can also inhibit a wide variety of cytokines in vivo.


Asunto(s)
Proteínas Portadoras/genética , Citocinas/antagonistas & inhibidores , Homeostasis/inmunología , Linfopenia/genética , Linfopenia/inmunología , Proteínas Represoras , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/patología , Animales , Apoptosis/genética , Apoptosis/inmunología , Proteínas Portadoras/fisiología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Citocinas/deficiencia , Citocinas/genética , Femenino , Homeostasis/genética , Memoria Inmunológica/genética , Inmunofenotipificación , Janus Quinasa 3 , Activación de Linfocitos/genética , Recuento de Linfocitos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/genética , Linfopenia/patología , Ratones , Ratones Transgénicos , Embarazo , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Receptores de Citocinas/deficiencia , Receptores de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas , Linfocitos T/enzimología , Linfocitos T/inmunología , Linfocitos T/metabolismo
20.
Proc Natl Acad Sci U S A ; 97(10): 5405-10, 2000 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-10792035

RESUMEN

Signal transducers and activators of transcription (STAT)-induced STAT inhibitor-1 [SSI-1; also known as suppressor of cytokine signaling-1 (SOCS-1)] was identified as a negative feedback regulator of Janus kinase-STAT signaling. We previously generated mice lacking the SSI-1 gene (SSI-1 -/-) and showed that thymocytes and splenocytes in SSI-1 -/- mice underwent accelerated apoptosis. In this paper, we show that murine embryonic fibroblasts lacking the SSI-1 gene are more sensitive than their littermate controls to tumor necrosis factor-alpha (TNF-alpha)-induced cell death. In addition, L929 cells forced to express SSI-1 (L929/SSI-1), but not SSI-3 or SOCS-5, are resistant to TNF-alpha-induced cell death. Furthermore L929/SSI-1 cells treated with TNF-alpha sustain the activation of p38 mitogen-activated protein (MAP) kinase. In contrast, SSI-1 -/- murine embryonic fibroblasts treated with TNF-alpha show hardly any activation of p38 MAP kinase. These findings suggest that SSI-1 suppresses TNF-alpha-induced cell death, which is mediated by p38 MAP kinase signaling.


Asunto(s)
Proteínas Portadoras/fisiología , Muerte Celular/fisiología , Citocinas/farmacología , Proteínas de Unión al ADN/metabolismo , Inhibidores Enzimáticos/metabolismo , Fibroblastos/fisiología , Proteínas Represoras , Transactivadores/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Factor de Necrosis Tumoral alfa/fisiología , Androstadienos/farmacología , Animales , Proteínas Portadoras/genética , Caspasa 3 , Inhibidores de Caspasas , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Embrión de Mamíferos , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Imidazoles/farmacología , Interferón gamma/farmacología , Interleucina-1/farmacología , Cinética , Células L , Ratones , Ratones Noqueados , Piridinas/farmacología , Proteínas Recombinantes/farmacología , Factor de Transcripción STAT1 , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas , Transactivadores/deficiencia , Transactivadores/genética , Transfección , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Wortmanina
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