Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Radiodermite/diagnóstico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Relação Dose-Resposta à Radiação , Eritema/diagnóstico , Eritema/etiologia , Eritema/patologia , Humanos , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/radioterapia , Masculino , Radiodermite/induzido quimicamente , Radiodermite/etiologia , Radiodermite/patologia , Fatores de RiscoAssuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Epistaxe/tratamento farmacológico , Telangiectasia Hemorrágica Hereditária/complicações , Administração Intranasal , Aerossóis , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/economia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/economia , Bevacizumab , Cauterização , Terapia Combinada , Avaliação de Medicamentos , Epistaxe/etiologia , Epistaxe/cirurgia , Feminino , Humanos , Lasers de Corante/uso terapêutico , Masculino , Mucosa Nasal/efeitos dos fármacos , RecidivaRESUMO
Initiation of adaptive immunity requires activation of dendritic cells (DC) by "danger" signals. This study examines the functional consequences of activating a cellular stress response in human DC. Anisomycin, a potent inducer of this "stress" response, selectively activates p38 kinase in DC at low concentrations, and both p38 kinases and JNKs at higher concentrations. Activation of p38, was accompanied by an increase in the potency of dendritic cells to activate T cells. In contrast to LPS, anisomycin had no effect on the expression of several DC activation markers. Anisomycin synergised with LPS in driving release of IL-12 and TNF-alpha. Anisomycin also enhanced the formation of clusters between DC and T cells. Enhanced cytokine release and clustering were both inhibited by the selective p38 alpha and p38 beta inhibitor SB203580. This study demonstrates that the cellular stress response, mediated via p38 kinases, plays an important role in the regulation of several aspects of DC function.
Assuntos
Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Anisomicina/toxicidade , Apresentação de Antígeno , Células Dendríticas/efeitos dos fármacos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Humanos , Técnicas In Vitro , Interleucina-12/biossíntese , Interleucina-6/biossíntese , Proteínas Quinases JNK Ativadas por Mitógeno , Lipopolissacarídeos/toxicidade , Modelos Imunológicos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
The basis for this study was the "injury hypothesis," which holds that release of micro-environmental constituents, such as reactive oxygen species and oxidants, acts as a signal, and potential activator, of dendritic cell (DC)-mediated antigen presentation. Following this oxidative stress, dityrosine containing cross-linked proteins, advanced oxidation protein products (AOPP), are known to be generated, and we proposed that they may serve as moieties that mediate such signals. Therefore, the effect of AOPP on DCs has been examined in vitro. There were no AOPP-induced changes in DC phenotype as judged by expression of typical surface costimulatory molecules. However, at higher cell concentrations AOPP-treated DCs were more potent inducers in an oxidative mitogenesis assay than controls. Thus, AOPP may act like superantigens, allowing for bypass of upregulation of costimulation, and, either alone or in synergy with oxidants themselves, serving as amplifiers of DC function.