RESUMO
High-mobility group-1 (HMG-1), an abundant, highly conserved cellular protein, is widely known as a nuclear DNA-binding protein that stabilizes nucleosome formation, facilitates gene transcription, and regulates the activity of steroid hormone receptors. We discovered that HMG-1 is a late mediator of delayed endotoxin lethality. When released by activated monocytes, it participates in the development of lethality and it activates downstream cytokine release. This review covers the general features of HMG-1 and its newly appreciated role as a cytokine.
Assuntos
Proteínas de Transporte/fisiologia , Citocinas/fisiologia , Endotoxemia/metabolismo , Endotoxinas/toxicidade , Proteínas de Grupo de Alta Mobilidade/fisiologia , Monócitos/metabolismo , Reação de Fase Aguda/etiologia , Sequência de Aminoácidos , Animais , Proteínas de Transporte/sangue , Proteínas de Transporte/química , Proteínas de Transporte/genética , Proteínas de Transporte/toxicidade , Drosophila melanogaster/metabolismo , Endotoxinas/farmacologia , Proteína HMGB1 , Proteínas de Grupo de Alta Mobilidade/sangue , Proteínas de Grupo de Alta Mobilidade/química , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/toxicidade , Humanos , Mediadores da Inflamação/metabolismo , Proteínas de Insetos/química , Proteínas de Insetos/fisiologia , Interleucina-1/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Modelos Biológicos , Dados de Sequência Molecular , Monócitos/efeitos dos fármacos , Família Multigênica , Adeno-Hipófise/citologia , Processamento de Proteína Pós-Traducional , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/metabolismo , Choque Séptico/etiologia , Choque Séptico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Especificidade da Espécie , Fator de Necrose Tumoral alfa/farmacologia , Vertebrados/metabolismoRESUMO
Acute inflammatory lung injury is often a delayed complication of critical illness and is associated with increased mortality. High mobility group-1 (HMG-1) protein, in addition to its role as a transcriptional regulatory factor, has recently been identified as a late mediator of endotoxin lethality. In the present studies, HMG-1 given intratracheally produced acute inflammatory injury to the lungs, with neutrophil accumulation, the development of lung edema, and increased pulmonary production of IL-1beta, TNF-alpha, and macrophage-inflammatory protein-2. In endotoxin-induced acute lung inflammation, administration of anti-HMG-1 Abs either before or after endotoxin exposure decreased the migration of neutrophils to the lungs as well as lung edema. These protective effects of anti-HMG-1 were specific, because pulmonary levels of IL-1beta, TNF-alpha, or macrophage-inflammatory protein-2 were not decreased after therapy with anti-HMG-1. Together, these findings indicate that HMG-1 is a distal mediator of acute inflammatory lung injury.
Assuntos
Adjuvantes Imunológicos/toxicidade , Endotoxemia/imunologia , Endotoxemia/patologia , Proteínas de Grupo de Alta Mobilidade/toxicidade , Animais , Quimiocina CXCL2 , Quimiocinas/metabolismo , Modelos Animais de Doenças , Endotoxemia/metabolismo , Endotoxemia/mortalidade , Endotoxinas/toxicidade , Proteínas de Grupo de Alta Mobilidade/imunologia , Humanos , Soros Imunes/administração & dosagem , Imuno-Histoquímica , Interleucina-1/metabolismo , Intubação Intratraqueal , Pulmão/química , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Especificidade de Órgãos/imunologia , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.