RESUMEN
SIGNR1, a member of a new family of mouse C-type lectins, is expressed at high levels in macrophages (Mphi) within the splenic marginal zone, lymph node medulla, and in some strains, in peritoneal cavity. We previously reported that SIGNR1 captures gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium, as well as Candida albicans. We have now investigated the precise ligands and innate responses that involve SIGNR1. The interaction of SIGNR1 with FITC-dextran and E. coli was completely inhibited by LPS from E. coli and Salmonella minnesota. Using LPS from various types of rough mutants of Salmonella, we found that SIGNR1 primarily recognizes oligosaccharides in the non-reductive end of the LPS core region. In transfectants, expression of SIGNR1 enhanced the oligomerization of Toll-like receptor (TLR) 4 molecules as well as the degradation of IkappaB-alpha after stimulation with E. coli under low-serum conditions. The enhanced TLR4 oligomerization was inhibited by pre-treatment of the cells with anti-SIGNR1 mAb or with mannan. A physical association between SIGNR1 and the TLR4-MD-2 complex was also observed by immunoprecipitation. Finally, we found that transfection of SIGNR1 into the macrophage-like RAW264.7 cells resulted in significant augmentation of cytokine production. These results suggest that SIGNR1 associates with TLR4 to capture gram-negative bacteria and facilitate signal transduction to activate innate M responses.
Asunto(s)
Moléculas de Adhesión Celular/inmunología , Escherichia coli/inmunología , Lectinas Tipo C/inmunología , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Glicoproteínas de Membrana/inmunología , Receptores de Superficie Celular/inmunología , Salmonella/inmunología , Transducción de Señal/inmunología , Animales , Línea Celular , Citocinas/biosíntesis , Femenino , Expresión Génica , Lectinas Tipo C/genética , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/inmunologíaAsunto(s)
Humanos , Ciclopropanos/farmacología , Hipoglicinas/envenenamiento , Vómitos/etiología , Intoxicación por Plantas , Ácido Graso Desaturasas/antagonistas & inhibidores , Ácidos Grasos/sangre , Ácidos Grasos/orina , Hipoglicinas/orina , Jamaica , Oxidorreductasas/antagonistas & inhibidores , Vómitos/etiologíaAsunto(s)
Humanos , Lactante , Preescolar , Niño , Adolescente , Adulto , Ratas , 21003 , Masculino , Femenino , Hipoglicinas/efectos adversos , Hipoglicinas/metabolismo , Hipoglicinas/envenenamiento , Enfermedades Transmitidas por los Alimentos/diagnóstico , Intoxicación por Plantas/etiología , Intoxicación por Plantas/patología , Intoxicación por Plantas/terapia , Jamaica , Síndrome de Reye/diagnóstico , Síndrome de Reye/etiología , Vómitos , Hipoglucemia/etiología , FrutasRESUMEN
We identified methylenecyclopropylacetic acid, a known metabolite of hypoglycin A, in the urine of two patients with Jamaican vomiting sickness. Excretion of unusual dicarboxylic acids such as 2-ethylmalonic, 2-methylsuccinic, glutaric, adipic and dicarboxylic acids with eight and 10 carbon chains were also detected in both patients. The amounts of these dicarboxylic acids were 70 to 1000 times higher than normal. These metabolities have also been identified in urine of hypoglycin-treated rats. This evidence links hypoglycin A to Jamaican vomiting sickness as its causative agent. Urinary excretion of short-chain fatty acids was also increased up to 300 times higher than normal. These results indicate that, despite their clinical and histological similarities, the cause and biochemical mechanisms of Jamaican vomiting sickness differ distinctly from those of Reye's syndrome in which these abnormal urinary metabolities are not appreciably increased.(AU)
Asunto(s)
Humanos , Preescolar , Ratas , 21003 , Femenino , Intoxicación por Plantas , Vómitos/etiología , Hipoglicinas/envenenamiento , Ciclopropanos/metabolismo , Diagnóstico Diferencial , Ácidos Dicarboxílicos/orina , Ácidos Grasos Volátiles/sangre , Ácidos Grasos Volátiles/orina , Enfermedades Transmitidas por los Alimentos/etiología , Enfermedades Transmitidas por los Alimentos/orina , Gluconeogénesis , Hidroxiácidos/orina , Hipoglucemia/etiología , Jamaica , Síndrome de Reye/diagnóstico , Toxinas Biológicas/metabolismo , Valeratos/orinaRESUMEN
Large amounts of ethylmalonic acid have been identified in urines from two patients with the vomiting sickness of Jamaica. The amounts were 178 and 882æg per mg creatinine which are 70 and 350 times, respectively, over control values. Other short and medium chain dicarboxylic acids including glutaric and adipic acids and those with eight and ten carbon chain, saturated and cis-unsaturated, were also detected in large quantities as in the case of hypoglycin treated rats' urine. However, the large increase of urinary ethylmalonic acid in these two human cases is in a sharp contrast to the findings in hypoglycin treated rats in which urinary ethylmalonic acid increased only 3 times over control. It appears that ethylmalonic acid is produced in the cases with the vomiting sickness of Jamaica by carboxylation of n-butyryl-CoA which is not oxidised further due to the inhibition by hypoglycin A. In case of hypoglycin-treated rats, n-butyryl-CoA is mainly conjugated with glycine or deacylated to free butyric acid.(Summary)