RESUMEN
Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the Hmgb1 gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced Il24 mRNA, expression was also augmented in the Hmgb1-deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the Il24 gene in the hmgb1-deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.
Asunto(s)
Ensamble y Desensamble de Cromatina , Dermatitis Alérgica por Contacto/metabolismo , Proteína HMGB1/metabolismo , Histonas/metabolismo , Interleucinas/metabolismo , Queratinocitos/metabolismo , Animales , Dermatitis Alérgica por Contacto/genética , Dermatitis Alérgica por Contacto/prevención & control , Dinitrofluorobenceno/toxicidad , Modelos Animales de Enfermedad , Oído/patología , Eliminación de Gen , Regulación de la Expresión Génica/genética , Proteína HMGB1/deficiencia , Proteína HMGB1/genética , Inflamación/genética , Inflamación/metabolismo , Interleucina-4/farmacología , Interleucinas/genética , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas , Piel/inmunología , Piel/metabolismo , Piel/patología , Quimera por TrasplanteAsunto(s)
Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/efectos adversos , Síndromes Paraneoplásicos/inducido químicamente , Pénfigo/inducido químicamente , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Clorhidrato de Bendamustina , Erupciones por Medicamentos/diagnóstico , Femenino , Humanos , Compuestos de Mostaza Nitrogenada/administración & dosificación , Síndromes Paraneoplásicos/diagnóstico , Pénfigo/diagnóstico , Recurrencia , Rituximab , Terapia Recuperativa/efectos adversosRESUMEN
BACKGROUND: High mobility group box-1 (HMGB1) is a ubiquitously expressed non-histone nuclear protein which acts as a danger signal when released from cells. HMGB1, which is associated with inflammation, angiogenesis, and T helper (Th)2 polarization, contributes to the development of various inflammatory diseases and malignancies. However, it remains to be determined whether HMGB1 is involved in cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To investigate the role of HMGB1 in CTCL. MATERIALS & METHODS: Serum HMGB1 levels were measured in patients with CTCL and healthy controls using an enzyme-linked immunosorbent assay. HMGB1 messenger RNA (mRNA) expression in CTCL and normal skin was examined by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. Moreover, we analysed correlations between the levels of HMGB1 and other cytokines and chemokines, laboratory data, disease activity, and prognosis. RESULTS: HMGB1 levels were significantly higher in sera of CTCL patients than those of normal controls and correlated with serum levels of soluble interleukin-2 receptor, lactate dehydrogenase, thymus and activation-regulated chemokine, and the number of eosinophils in peripheral blood. Serum HMGB1 levels also reflected disease activity and prognosis for each patient with CTCL. HMGB1 mRNA levels in CTCL lesional skin were significantly elevated and correlated with IL-4, IL-10, IL-19, and angiogenin mRNA levels. Immunohistochemical staining revealed that HMGB1 was expressed not only in the nucleus but also in the cytoplasm of various cells in CTCL lesional skin. CONCLUSION: These results suggest that enhanced HMGB1 expression may contribute to the progression of CTCL through Th2 polarization and promotion of angiogenesis.
Asunto(s)
Biomarcadores de Tumor/sangre , Proteína HMGB1/metabolismo , Linfoma Cutáneo de Células T/sangre , Linfoma Cutáneo de Células T/patología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patología , Anciano , Biopsia con Aguja , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Linfoma Cutáneo de Células T/mortalidad , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Valores de Referencia , Neoplasias Cutáneas/mortalidad , Estadísticas no Paramétricas , Análisis de SupervivenciaRESUMEN
A 56-year-old male presented with fulminant subdural empyema manifesting as rhinorrhea, periorbital cellulitis, fever, convulsions, and consciousness disturbance. Neuroimaging showed pansinusitis with skull destruction and extensive subdural empyema. Decompressive craniectomy, irrigation of the empyema, and subdural drainage were performed. Endoscopic sinus surgery was performed to remove the source of infection at the same time. Streptococcus milleri was cultured from the pus. Continuous irrigation of the subdural space with saline containing gentamicin for 7 days resulted in prompt elimination of pus and debris. The patient was discharged with only a slight neurological deficit.