RESUMEN
Triclosan, a commonly used antimicrobial compound, has been measured in aquatic systems worldwide. This study exposed marine species to triclosan to examine effects primarily on survival and to investigate the formation of the degradation product, methyl-triclosan, in the estuarine environment. Acute toxicity was assessed using the bacterium Vibrio fischeri, the phytoplankton species Dunaliella tertiolecta, and three life stages of the grass shrimp Palaemonetes pugio. P. pugio larvae were more sensitive to triclosan than adult shrimp or embryos. Acute aqueous toxicity values (96 h LC50) were 305 microg/L for adult shrimp, 154 microg/L for larvae, and 651 microg/L for embryos. The presence of sediment decreased triclosan toxicity in adult shrimp (24 h LC50s were 620 microg/L with sediment, and 482 microg/L without sediment). The bacterium was more sensitive to triclosan than the grass shrimp, with a 15 min aqueous IC50 value of 53 microg/L and a 15 min spiked sediment IC50 value of 616 microg/kg. The phytoplankton species was the most sensitive species tested, with a 96 h EC50 value of 3.55 microg/L. Adult grass shrimp were found to accumulate methyl-triclosan after a 14-day exposure to 100 microg/L triclosan, indicating formation of this metabolite in a seawater environment and its potential to bioaccumulate in higher organisms. Triclosan was detected in limited surface water sampling of Charleston Harbor, SC at a maximum concentration of 0.001 microg/L, substantially lower than the determined toxicity values. These findings suggest triclosan poses low acute toxicity risk to estuarine organisms; however, the potential for chronic, sublethal, and metabolite effects should be investigated.
Asunto(s)
Antiinfecciosos/toxicidad , Triclosán/análogos & derivados , Contaminantes Químicos del Agua/toxicidad , Aliivibrio fischeri/efectos de los fármacos , Animales , Antiinfecciosos/análisis , Antiinfecciosos/metabolismo , Monitoreo del Ambiente , Dosificación Letal Mediana , Palaemonidae/efectos de los fármacos , Fitoplancton/efectos de los fármacos , South Carolina , Triclosán/análisis , Triclosán/metabolismo , Triclosán/toxicidad , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/metabolismoRESUMEN
The role of NF-kappaB-inducing kinase (NIK) in cytokine signaling remains controversial. To identify the physiologic functions of NIK, we disrupted the NIK locus by gene targeting. Although NIK-/- mice displayed abnormalities in both lymphoid tissue development and antibody responses, NIK-/- cells manifested normal NF-kappaB DNA binding activity when treated with a variety of cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1), and lymphotoxin-beta (LTbeta). However, NIK was selectively required for gene transcription induced through ligation of LTbeta receptor but not TNF receptors. These results reveal that NIK regulates the transcriptional activity of NF-kappaB in a receptor-restricted manner.
Asunto(s)
FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Transcripción Genética , Animales , Anticuerpos Monoclonales , Linfocitos B/metabolismo , Células Cultivadas , ADN/metabolismo , Fibroblastos/metabolismo , Marcación de Gen , Genes Reporteros , Interleucina-1/metabolismo , Interleucina-1/farmacología , Ligandos , Tejido Linfoide/anomalías , Receptor beta de Linfotoxina , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , Proteínas Serina-Treonina Quinasas/genética , Receptores del Factor de Necrosis Tumoral/inmunología , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Quinasa de Factor Nuclear kappa BRESUMEN
Herein we report the generation of mice lacking the ubiquitously expressed Janus kinase, Jak1. Jak1-/- mice are runted at birth, fail to nurse, and die perinatally. Although Jak1-/- cells are responsive to many cytokines, they fail to manifest biologic responses to cytokines that bind to three distinct families of cytokine receptors. These include all class II cytokine receptors, cytokine receptors that utilize the gamma(c) subunit for signaling, and the family of cytokine receptors that depend on the gp130 subunit for signaling. Our results thus demonstrate that Jak1 plays an essential and nonredundant role in promoting biologic responses induced by a select subset of cytokine receptors, including those in which Jak utilization was thought to be nonspecific.
Asunto(s)
Antígenos CD/fisiología , Citocinas/farmacología , Glicoproteínas de Membrana/fisiología , Proteínas Tirosina Quinasas/fisiología , Receptores de Citocinas/fisiología , Animales , Peso al Nacer , Células Cultivadas , Receptor gp130 de Citocinas , Proteínas de Unión al ADN/metabolismo , Fibroblastos , Antígenos de Histocompatibilidad Clase I/análisis , Janus Quinasa 1 , Leucopoyesis , Ligandos , Macrófagos/citología , Ratones , Ratones Noqueados , Miocardio/citología , Neuronas Aferentes/citología , Tamaño de los Órganos , Proteínas Tirosina Quinasas/genética , Factor de Transcripción STAT3 , Transducción de Señal/fisiología , Bazo/citología , Bazo/inmunología , Timo/citología , Timo/patología , Transactivadores/metabolismoRESUMEN
Recently, we reported the generation and characterization of hamster mAbs specific for the murine p55 and p75 TNF receptors. Upon characterizing these mAbs in vivo, we discovered that administration of TNF receptor-specific mAb to normal mice resulted in the linear accumulation of the appropriate class of soluble TNF receptor in the circulation. The mechanism underlying soluble receptor accumulation was found to be due to an abrogation of the clearance of constitutively shed soluble receptor by receptor-specific mAb. Levels of p55 or p75 accumulated in the presence of nonblocking, nonagonistic TNF receptor mAb were capable of inhibiting murine TNF-induced responses in vivo. These results document that both p55 and p75 are constitutively shed in substantial amounts in vivo and suggest that the process of constitutive TNF receptor shedding plays an important role in regulating TNF activity under physiologic conditions.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Receptores del Factor de Necrosis Tumoral/metabolismo , Animales , Cricetinae , Femenino , Ratones , Ratones Endogámicos BALB C , Receptores del Factor de Necrosis Tumoral/inmunologíaRESUMEN
Monoclonal antibodies (mAbs) specific for the murine p55 and p75 tumor necrosis factor (TNF) receptors were produced after immunization of Armenian hamsters with the purified soluble extracellular domains of each receptor protein. Four p55- (55R) and five p75 (TR75)-reactive mAbs immunoprecipitated the appropriate receptor from the surface of L929 cells. None of the mAbs cross-reacted with the other TNF receptor form. The mAbs were functionally characterized by their ability to inhibit ligand binding and influence TNF-dependent L cell cytolytic activity or proliferation of the murine cytolytic T cell clone CT6. One p55-specific mAb, 55R-593, displayed agonist activity, while two other p55-specific mAbs (55R-170 and -176) were found to be TNF antagonists. The fourth mAb (55R-286) had no functional effects on cells. Several antibodies specific for the p75 TNF receptor partially inhibited recombinant murine TNF-alpha-dependent cytolytic activity (60%). Blocking mAbs specific for p75 but not anti-p55 inhibited TNF-mediated proliferation of CT6 T cells. When used in vivo, p55- but not p75-specific mAbs protected mice from lethal endotoxin shock and blocked development of a protective response against Listeria monocytogenes infection. In contrast, both p55 and p75 mAbs individually blocked development of skin necrosis in mice treated with murine TNF-alpha. These data thus demonstrate the utility of the two families of murine TNF receptor-specific mAbs and identify a novel function of the p75 TNF receptor in vivo.