RESUMEN
The U.S. Forest Service has a long history of providing termiticide efficacy data used for product registration and labeling. Four primary test sites (Arizona and Florida, Mississippi, and South Carolina [hereafter southeast]) have been used for this purpose. Various parameters of termite attack at water-only control plots were examined in this study to assess the relative pressures of termites at each site. Termiticide studies installed between 1971 and 2001 by using ground board (GB) and concrete slab (CS) test methods were included. GB control plots were attacked 85% of the time in the southeast, about twice the rate observed in Arizona (43%). CS plots were attacked 59-70% of the time in the southeast, significantly higher than in Arizona (43%). Termites were slower to initiate attack at control plots in Arizona compared with the southeast, and they were up to twice as slow at GB controls. Once initial attack began, GB plots were reattacked at higher percentages in the southeast (89-90%) than in Arizona (67%). Reattack at CS plots ranged from 65% in Arizona and South Carolina to 76% in Mississippi. Termites caused less damage to wooden blocks in control plots in Arizona than the southeast. Attack rates at controls generally declined during the 1990s, but these rates have rebounded since 2000, except at CS plots in Arizona and South Carolina. Statistical analysis of attacks at plots treated with chlorpyrifos, cypermethrin, fenvalerate, and permethrin also was undertaken. Time to initial termite attack (failure) of the organophosphate chlorpyrifos was generally shorter in Arizona than in the southeast, whereas time to initial attack in plots treated with one of three pyrethroids (cypermethrin, fenvalerate, and permethrin) was generally longer in Arizona.
Asunto(s)
Insecticidas , Isópteros , Pruebas de Toxicidad , Animales , Conducta Alimentaria , Agricultura Forestal , Isópteros/fisiología , Estados UnidosRESUMEN
Laboratory and field studies were conducted to determine the persistence and efficacy of termiticides used as preconstruction treatments against subterranean termites. Bifenthrin (0.067%), chlorpyrifos (0.75%), and imidacloprid (0.05%) ([AI]; wt:wt) were applied to soil beneath a monolithic concrete slab at their minimum labeled rates. Soil samples were taken from three depths (0-2.5, 2.6-7.6, and 7.7-15.2 cm) at six sampling times (0, 3, 6, 9, 12 and 48 mo) from sites in Harrison and Oktibbeha counties in Mississippi. Residue analyses were conducted on the 0-2.5- and 2.6-7.5-cm depths, and bioassays were conducted using all three depths. In field studies, significant termiticide degradation occurred between sampling times 0 and 48 mo for all termiticides. At all sampling times, the top 2.5 cm of soil contained more termiticide than the other depths. Time to 50% dissipation of termiticide in the 0-2.5-cm depth was 9, 6, and 2 mo for bifenthrin, chlorpyrifos, and imidacloprid, respectively. Termite mortalities in contact bioassays remained high for bifenthrin and chlorpyrifos throughout the 48-mo sampling period; however, mortality of termites exposed to imidacloprid-treated soil dropped after the initial sampling. Termites readily penetrated all termiticide-treated soil in bioassays of 52-mm soil cores at 48 mo. Percentage of mortality in these bioassays was 15, 43, and 13 for bifenthrin, chlorpyrifos, and imidacloprid respectively.
Asunto(s)
Cloropirifos/farmacología , Imidazoles/farmacología , Isópteros/efectos de los fármacos , Residuos de Plaguicidas , Piretrinas/farmacología , Suelo/análisis , Animales , Cloropirifos/química , Imidazoles/química , Insecticidas/química , Insecticidas/farmacología , Mississippi , Neonicotinoides , Nitrocompuestos , Piretrinas/químicaRESUMEN
Cytokines produced by antigen-presenting cells are known to affect the development and cytokine profile of T cells. The immune response modifiers imiquimod and R-848 were previously shown to stimulate human and mouse cultures to secrete interferon-alpha. Results from the present study demonstrate that R-848 and imiquimod are capable of inducing interleukin-12 and interferon-gamma in mouse and human cell cultures. Both CD4(+) and CD8(+) T lymphocytes were responsible for producing IFN-gamma following stimulation with R-848. Macrophages were required for induction of interferon-gamma by R-848 and the cytokines IFN-alpha and IL-12 mediated this response. R-848 and imiquimod were also found to inhibit IL-4 and IL-5 production in mouse and human culture systems. The inhibition of IL-5 in response to R-848 is seen in cultures containing CD4(+) lymphocytes and macrophages and is mediated in part by IFN-alpha. These data suggest that imiquimod and R-848 may have clinical utility in diseases where cell-mediated immune responses are important and in diseases associated with overexpression of IL-4 or IL-5 such as atopic disease.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Aminoquinolinas/farmacología , Citocinas/biosíntesis , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Animales , Humanos , Imiquimod , Interferón-alfa/biosíntesis , Interferón gamma/biosíntesis , Interleucina-12/biosíntesis , Interleucina-5/biosíntesis , Masculino , Ratones , Ratones Endogámicos BALB C , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Electrical synapses, or gap junctions, are widely distributed in the vertebrate retina and are thought to play critical roles in the transmission and coding of visual signals. To investigate the molecular basis of this form of neural communication in the retina, we have isolated, characterized, and functionally expressed a cDNA for a gap junction channel derived from the retina of the teleost fish Danio aquipinnatus (giant danio). The cDNA contained an open reading frame of 1146 nucleotides encoding a connexin with a predicted molecular mass of 43.3 kDa which shared extensive identity with Rattus norvegicus Cx43 (78%). This protein (DACX43) contained several consensus phosphorylation sequences in the c-terminal region, some of which are conserved among Cx43 orthologs. RNA blot hybridization revealed that DACX43 was expressed in the brain as well as in the retina. In addition, Southern analysis suggested that there are multiple copies of DACX43, or other closely related sequences, in the Danio aquipinnatus genome. When DACX43 was expressed by stable transfection in gap-junction-deficient mouse N2A neuroblastoma cells, functional gap junctions were formed as indicated by dual whole-cell recordings of electrical coupling. We conclude that DACX43 is a connexin43 ortholog, which is expressed in the retina of Danio aquipinnatus, and when translated is able to form functional gap junction channels.
Asunto(s)
Clonación Molecular , Conexina 43/genética , Conexina 43/metabolismo , Uniones Comunicantes/metabolismo , Retina/metabolismo , Pez Cebra/fisiología , Secuencia de Aminoácidos , Animales , Conexinas/química , Conexinas/genética , Ratones , Datos de Secuencia Molecular , Ratas/genética , Homología de Secuencia de Aminoácido , Células Tumorales Cultivadas , Pez Cebra/genéticaRESUMEN
ALDARA (imiquimod cream 5%) recently became available for the treatment of genital and perianal warts; however, the topical mechanism of action of imiquimod is not fully understood. Imiquimod, and its analogs R-842, S-27609, and S-28463, are potent anti-viral and anti-tumor agents in animal models. Much of the biologic activity of these compounds can be attributed to the induction of cytokines, including interferon-alpha, tumor necrosis factor-alpha, interleukins-1, -6, -8, and others. This study was performed to characterize the response of mice and rats to topical application of imiquimod and S-28463 and also to evaluate these agents in cultures of murine and human skin cells. Topical administration of imiquimod or S-28463 to the flanks of hairless mice and rats leads to increases in local concentrations of interferon and tumor necrosis factor in the skin. The concentrations of interferon and tumor necrosis factor were higher at the site of drug application than in skin from the contralateral flank or skin from untreated animals. Interferon-alpha mRNA levels were also elevated in the skin of mice after topical application of either imiquimod or S-28463. In vitro, both imiquimod and S-28463 induced increases in interferon and tumor necrosis factor in cultures of cells isolated from hairless mouse skin. Imiquimod also increased interleukin-8 concentrations in human keratinocyte and fibroblast cultures, whereas S-28463 induced increases in tumor necrosis factor in fibroblast cultures. These results demonstrate that imiquimod and S-28463 stimulate production of cytokines in the skin after topical application, which may play a major role in its activity in genital wart patients.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Aminoquinolinas/farmacología , Citocinas/metabolismo , Piel/metabolismo , Administración Tópica , Animales , Formación de Anticuerpos/efectos de los fármacos , Células Cultivadas , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Imiquimod , Interferón-alfa/genética , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Masculino , Melanocitos/efectos de los fármacos , Melanocitos/metabolismo , Ratones , Ratones Pelados , ARN Mensajero/metabolismo , Ratas , Ratas Desnudas , Piel/citología , Piel/efectos de los fármacosRESUMEN
Sprague-Dawley rats (200 g) were fed either a Mg-deficient or Mg-sufficient diet for 3 weeks. An enriched neutrophil fraction (> 85%) was isolated from the blood by sodium metrizoate/dextran gradient centrifugation. Using the superoxide dismutase. (SOD)-inhibitable cytochrome c reduction assay, the basal activity of neutrophils isolated from the Mg-deficient rats were found elevated 5 fold after two weeks, and up to approximately 7 fold after three weeks on the diet. Upon challenge by phorbol myristate acetate (PMA), unlike the Mg-sufficient cells, the Mg-deficient cells exhibited no significant activation. Treatment of the Mg-deficient rats with the nitric oxide (NO)-synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) in the drinking water, significantly attenuated the basal superoxide producing activity of the neutrophils and partially restored its response to PMA challenge. In association with the neutrophil activation. Mg-deficiency resulted in 70% decrease in plasma glutathione and 220% increase in Fe-promoted, thiobarbituric acid reactive substance (TBARS) levels; both changes were significantly attenuated by L-NAME treatment. The results suggest that neutrophils from Mg-deficient rats are activated endogenously to generate oxy-radicals which might directly mediate the in vivo peroxidative indices during Mg-deficiency. Furthermore, the neutrophil activity was lowered by NO-synthase inhibition suggesting that NO overproduction during Mg-deficiency participates in the neutrophil activation process.
Asunto(s)
Glutatión/sangre , Deficiencia de Magnesio/metabolismo , Activación Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Animales , Carcinógenos/farmacología , Inhibidores Enzimáticos/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Neutrófilos/enzimología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Factores de TiempoRESUMEN
Magnesium deficiency (MgD) has been associated with production of reactive oxygen species, cytokines, and eicosanoids, as well as vascular compromise in vivo. Although MgD-induced inflammatory change occurs during "chronic" MgD in vivo, acute MgD may also affect the vasculature and consequently, predispose endothelial cells (EC) to perturbations associated with chronic MgD. As oxyradical production is a significant component of chronic MgD, we examined the effect of acute MgD on EC oxidant production in vitro. In addition we determined EC; pH, mitochondrial function, lysosomal integrity and general cellular antioxidant capacity. Decreasing Mg2+ (< or = 250microM) significantlyincreased EC oxidant production relative to control Mg2+ (1000microM). MgD-induced oxidant production, occurring within 30min, was attenuated by EC treatment with oxyradical scavengers and inhibitors of eicosanoid biosynthesis. Coincident with increased oxidant production were reductions in intracellular glutathione (GSH) and corresponding EC alkalinization. These data suggest that acute MgD is sufficient for induction of EC oxidant production, the extent of which may determine, at least in part, the extent of EC dysfunction/injury associated with chronic MgD.
Asunto(s)
Endotelio Vascular/metabolismo , Deficiencia de Magnesio/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Enfermedad Aguda , Animales , Aorta , Catalasa/metabolismo , Bovinos , Supervivencia Celular , Células Cultivadas , Colorantes/metabolismo , Eicosanoides/biosíntesis , Endotelio Vascular/citología , Fluoresceínas/química , Fluorescencia , Colorantes Fluorescentes/química , Glutatión/metabolismo , Concentración de Iones de Hidrógeno , Lisosomas/metabolismo , Mitocondrias/fisiología , Rojo Neutro/metabolismo , Oxidación-Reducción , Rodamina 123 , Rodaminas/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
In rats, copper deficiency leads to low copper metalloenzyme activity, high serum cholesterol, and cardiovascular lesions. In humans, moderately low copper intake may be common, but the consequences remain largely uncertain. The present study examined the effects of copper supplementation (2 mg/d for 4 weeks in a copper/placebo crossover design) in 20 adult men with moderately high plasma cholesterol. End-point measurements were three copper enzyme activities, erythrocyte superoxide dismutase (SOD), plasma ceruloplasmin (Cp), and plasma diamine oxidase (DAO), and three parameters related to the risk of cardiovascular disease (CVD), plasma cholesterol, plasma lipoprotein (a) [Lp(a)], and lag times for very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) oxidation in vitro. Although copper had no significant effects on any parameter for the entire study group, it did significantly increase two enzyme activities (SOD and DAO), as well as lipoprotein oxidation lag times, in 10 subjects in the lower half of a median split for precopper values. Thus, copper supplementation appeared to influence some types of measurements in subjects beginning with less than median values.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/sangre , Enfermedades Cardiovasculares/epidemiología , Ceruloplasmina/análisis , Cobre/farmacología , Superóxido Dismutasa/sangre , Adulto , Enfermedades Cardiovasculares/sangre , Ceruloplasmina/metabolismo , Colesterol/sangre , Cobre/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Humanos , Peroxidación de Lípido , Lipoproteína(a)/sangre , Lipoproteínas LDL/metabolismo , Lipoproteínas VLDL/metabolismo , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Imiquimod, S-27609 and S-28463 are imidazoquinolines known to have antiviral and antitumour properties mediated by the induction of cytokines, in particular interferon alpha (IFN-alpha). This study evaluated these compounds for their ability to induce cytokines and cytokine specific messenger RNAs (mRNA) in cynomologus monkeys (Macaca fascicularis). Peripheral blood mononuclear cell (PBMC) cultures from monkeys produced IFN, interleukin 1beta (IL-1beta), IL-6 and IL-8 after treatment with imiquimod, S-27609 and S-28463. Tumour necrosis factor alpha (TNF-alpha) was also increased in cultures stimulated with S-27609 or S-28463. Monkey PBMCs stimulated with imiquimod, S-27609 and S-28463 showed increased mRNA levels of IFN-alpha, IL-1alpha, IL-6 and the IFN inducible protein, MxA above those seen in untreated cultures. S-27609 and S-28463 also had higher TNF-alpha mRNA expression than cultures not receiving drugs. When compared to lipopolysaccharide (LPS), S-27609 was less effective at inducing IL-1beta, IL-6, IL-8 and TNF-alpha but induced higher concentrations of IFN. Similar results were seen when evaluating cytokine mRNA levels. Upon oral administration to monkeys, S-28463 stimulated a dose-dependent increase in serum concentrations of IFN, TNF-alpha, IL-1 receptor antagonist (IL-1Ra) and IL-6, while imiquimod induced increases in IFN and IL-1Ra concentrations. Finally, skin biopsies from monkeys treated topically with S-28463 had increases over baseline in mRNA for IFN-alpha, IL-1alpha, IL-6 and MxA protein. The data show that imidazoquinolines induce cytokines and cytokine specific mRNA in cynomolgus monkeys. These results demonstrate the usefulness of human amplimers and human ELISAs in the detection of cytokine specific mRNAs and proteins in cynomolgus monkeys.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Aminoquinolinas/farmacología , Citocinas/biosíntesis , Inductores de Interferón/farmacología , Administración Oral , Administración Tópica , Animales , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Imiquimod , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Macaca fascicularis , Masculino , Modelos Químicos , ARN Mensajero/metabolismo , Piel/metabolismoRESUMEN
The effect of dietary Mg deficiency on nitric oxide (NO) production and its role in mediating oxidative depletion of red blood cell (RBC) glutathione in rats were investigated. Male Sprague-Dawley rats were placed on Mg-deficient or Mg-sufficient diets for up to 3 wk. Plasma nitrate plus nitrite levels, determined by the Escherichia coli reductase/Griess reagent procedures, increased 1.7-fold during the 1st wk and increased 2- to 2.4-fold during the 2nd and 3rd wk on the Mg-deficient diet. In association, substantial losses (approximately 50%) of RBC glutathione occurred during the 2nd and 3rd wk. Administration of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in drinking water (0.5 mg/ml) effectively blunted the increases in plasma nitrate/nitrite during Mg deficiency. Concomitantly, losses of RBC glutathione exhibited by Mg-deficient rats were significantly attenuated. Packed RBCs, obtained from Mg-deficient but not from Mg-sufficient animals, displayed a prominent nitrosyl hemoglobin signal detected by electron spin resonance spectroscopy; the signals of the samples from the L-NAME-treated Mg-deficient rats were greatly reduced. With isolated RBCs, losses of the glutathione could be induced directly by peroxynitrite or 3-morpholinosydnonimine, which generates NO + .O2-, but not by NO (from sodium nitroprusside) alone, in a concentration-dependent manner. The results clearly indicate that NO overproduction occurs and participates in RBC glutathione loss during Mg deficiency. Because neutrophil activation also occurs, we suggest that NO might interact with superoxide anions to form peroxynitrite, which then directly oxidizes RBC glutathione.
Asunto(s)
Eritrocitos/metabolismo , Glutatión/sangre , Deficiencia de Magnesio/metabolismo , Óxido Nítrico/biosíntesis , Animales , Espectroscopía de Resonancia por Spin del Electrón , Hemoglobinas/metabolismo , Masculino , Molsidomina/análogos & derivados , Molsidomina/farmacología , NG-Nitroarginina Metil Éster/farmacología , Nitratos/farmacología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Aumento de Peso/efectos de los fármacosRESUMEN
The first week of dietary magnesium deficiency in rodent models is characterized by the induction of raised levels of neuropeptides (substance P [SP] and calcitonin gene related peptide [CGRP]), followed shortly thereafter by inflammatory cytokine release. Since neuropeptides participate in neurogenic inflammation, we have proposed that the neurogenic inflammatory response plays a role in the pathology of magnesium deficiency. However, the association between the early neuropeptide release and the subsequent pathology in this model remains unclear. Peripheral blood T lymphocytes were obtained from Balb/c mice fed a magnesium-deficient diet (approximately 1.8 mmol Mg/kg), or the same diet supplemented with 20 mmol MgO/kg. These cells were incubated in medium containing 10(-10) to 10(-5) M SP, after which the cells were examined for expression of SP receptors and the supernatants were collected and examined by immunochemical techniques for the presence of T lymphocyte associated cytokines. SP stimulation induced the secretion of interleukin (IL)-2, 4, 5, 10, 12, 13 and interferon-gamma (IFN-gamma). T lymphocytes from magnesium-deficient animals, when compared to magnesium-sufficient ones, secreted increased levels of these cytokines. The secretion of these cytokines was maximal at either 5 days (IL-4, IL-5) or 7 days (II-2, IL-10, and IFN-gamma) of magnesium deficiency. This increased sensitivity to SP appears to be related to an increased expression of SP receptors on the surface of T lymphocytes during the first week of magnesium deficiency. These data indicate that SP released early during magnesium deficiency exerts a regulatory role on T lymphocyte cytokine production, especially those cytokines regulating mast cell and immune responses leading to the onset of an immunopathological state.
Asunto(s)
Citocinas/metabolismo , Deficiencia de Magnesio/inmunología , Deficiencia de Magnesio/fisiopatología , Sustancia P/farmacología , Linfocitos T/inmunología , Alimentación Animal , Animales , Citocinas/análisis , Citocinas/biosíntesis , Electroforesis Capilar , Ensayo de Inmunoadsorción Enzimática , Magnesio/administración & dosificación , Magnesio/sangre , Deficiencia de Magnesio/sangre , Masculino , Ratones , Ratones Endogámicos BALB C , Receptores de Neuroquinina-1/biosíntesis , Receptores de Neuroquinina-1/metabolismo , Sustancia P/sangre , Sustancia P/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Factores de TiempoRESUMEN
Recently, a new class of immunomodulating agents, represented by the molecules imiquimod and R-842, has demonstrated potent antiviral and antitumor activities in animal models. In this study, another representative of this class, S-28463 (4-amino-2-ethoxymethyl-alpha,alpha-dimethyl-1H-imidazo[4,5-c]quinoline- 1- ethanol) was evaluated for its immunomodulating and antiviral activities. S-28463 induced IFN and other cytokines in vivo in mice, rats, monkeys and in vitro in human peripheral blood mononuclear cell cultures. S-28463 showed potent antiviral activity against herpes simplex virus-challenged guinea pigs when given subcutaneously, dermally, or intravaginally 24 h before infection. Antiviral activity in guinea pigs correlated with the induction of serum 2',5'-oligoadenylate synthetase activity. Thus, S-28463, like the other imidazoquinolines, demonstrates potent antiviral and immunomodulating effects in a number of models.
Asunto(s)
Aminoquinolinas/farmacología , Antivirales/uso terapéutico , Herpesvirus Humano 1/efectos de los fármacos , 2',5'-Oligoadenilato Sintetasa/biosíntesis , Adyuvantes Inmunológicos/farmacología , Animales , Antivirales/farmacología , Citocinas/biosíntesis , Femenino , Cobayas , Herpes Simple/prevención & control , Inductores de Interferón/farmacología , Interferón-alfa/biosíntesis , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Imiquimod (R-837, S-26308) and the analogue S-27609 were evaluated for cytokine induction in human blood cells. Both compounds induced interferon-alpha (IFN), tumor necrosis factor-alpha (TNF), interleukin (IL)-1 beta, and IL-6 with S-27609 being 5 to 10 times more potent. Imiquimod and S-27609 also induced IL-1 alpha, IL-1 receptor antagonist, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), and macrophage inflammatory protein-1 alpha. The profile of cytokines induced by imiquimod and S-27609 was different from those seen with lipopolysaccharide and polyinosinic-polycytidylic acid. Kinetic studies with both imiquimod and S-27609 revealed induction of cytokines as early as 1-4 h after stimulation. Although most of the cytokines produced by S-27609 were secreted, significant concentrations of IL-1 alpha and IL-1 beta remained intracellular. Monocytes were largely responsible for the cytokines produced. Finally, S-27609-induced mRNA expression for TNF, IFN, and IL-8, and this induction did not require protein synthesis. Taken together, these studies extend previous findings by showing induction of additional cytokines and providing insight into the mechanism of cytokine induction by these molecules.
Asunto(s)
Adyuvantes Inmunológicos , Aminoquinolinas/farmacología , Citocinas/biosíntesis , Inductores de Interferón , Células Cultivadas , Cicloheximida/farmacología , Citocinas/genética , Dactinomicina/farmacología , Expresión Génica/efectos de los fármacos , Humanos , Imiquimod , Técnicas In Vitro , ARN Mensajero/genéticaRESUMEN
Imiquimod (R-837) and its analog, S-27609, belong to a class of imidazoquinolinamines that have potent antitumor and antiviral effects in animals. Much of their biologic activity is a result of the induction of cytokines, including interferon-alpha (IFN-alpha), tumor necrosis factor alpha (TNF), and others. In this study, the cells responsible for S-27609- and imiquimod-induced cytokine production were characterized. E rosette+ T cells were not the major cell population responsible for IFN-alpha and TNF in response to S-27609 or imiquimod. In contrast, E rosette- cells and unseparated PBMC produced similar concentrations of IFN-alpha and TNF in response to S-27609 and imiquimod. Elimination of monocytes by treatment with the lysosomotropic agent L-leucine methyl ester (LME) or depletion using antibody to CD14 and immunomagnetic beads abrogated IFN-alpha and TNF production induced by S-27609, imiquimod, or LPS but not poly(I)/(C). LME treatment also abolished interleukin (IL)-1 alpha, IL-beta, IL-6, and IL-8 production stimulated by S-27609 and imiquimod. Removal of HLA-DR+ or CD36+ monocytes also caused a significant reduction in S-27609- and imiquimod-induced IFN-alpha and TNF. Elimination of B cells, NK cells, and dendritic cells did not significantly reduce cytokine induction in response to S-27609. Thus, the cell population responsible for the majority of cytokine release in human PBMC in response to S-27609 and imiquimod is a E rosette-, CD14+, CD36+, HLA-DR+ monocyte.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Aminoquinolinas/farmacología , Citocinas/biosíntesis , Inductores de Interferón/farmacología , Antígenos CD36/sangre , Antígenos HLA-DR/inmunología , Humanos , Imiquimod , Receptores de Lipopolisacáridos/sangre , Monocitos/inmunologíaRESUMEN
The prospects for federal legislation preempting state corporate practice restrictions are unclear. The health care reform bill originally introduced by President Clinton contained a provision that would have preempted "any state law related to the corporate practice of medicine" insofar as it applied to the arrangements between non-fee-for-service health plans and their participating providers. H.R. 3600/S. 1757, 103d Cong., 1st Sess. 1407(b) (1993). Whether and in what form a preemption provision may survive the legislative process and see a Presidential signature remains to be seen. The particular fate of the federal legislation notwithstanding, however, health care executives can nevertheless remain confident that the legal treatment of the "corporate practice" of medicine will continue to be of vital concern as the various forms of health care organizations evolve in the ongoing struggle to deliver quality medicine at affordable prices.