RESUMO
Children with chronic inflammatory diseases experience growth failure and wasting. This may be due to growth hormone resistance caused by cytokine-induced suppression of growth hormone receptor (GHR) gene expression. However, the factors governing inflammatory regulation of GHR are not known. We have reported that Sp1 and Sp3 regulate hepatic GHR expression. We hypothesized that TNF-alpha suppresses GHR expression by inhibiting Sp1/Sp3 transactivators. LPS administration significantly reduced murine hepatic GHR expression, as well as Sp1 and Sp3 binding to GHR promoter cis elements. TNF-alpha was integral to this response, as LPS did not affect hepatic Sp1/Sp3 binding or GHR expression in TNF receptor 1-deficient mice. TNF-alpha treatment of BNL CL.2 mouse liver cells reduced Sp1 and Sp3 binding to a GHR promoter cis element and downregulated activity of a GHR promoter-driven luciferase reporter. Combined mutations within adjacent Sp elements eliminated GHR promoter suppression by TNF-alpha without affecting overall nuclear levels of Sp1 or Sp3 proteins. These studies demonstrate that murine GHR transcription is downregulated by LPS, primarily via TNF-alpha-dependent signaling. Evidence suggests that inhibition of Sp transactivator binding is involved. Further investigation of these mechanisms may identify novel strategies for preventing inflammatory suppression of growth.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Fígado/metabolismo , Podofilina/análogos & derivados , Receptores da Somatotropina/metabolismo , Fator de Transcrição Sp1/metabolismo , Transativadores/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Criança , Proteínas de Ligação a DNA/genética , Genes Reporter/genética , Hepatócitos/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/metabolismo , Plasmídeos/genética , Plasmídeos/metabolismo , Podofilotoxina/análogos & derivados , Regiões Promotoras Genéticas/genética , Receptores da Somatotropina/genética , Fator de Transcrição Sp1/genética , Transativadores/genéticaRESUMO
Thrombolytic therapy for unstable angina has not gained acceptance as a primary treatment for unstable angina (UA) despite the evidence showing a reduction in mortality when these agents are given for myocardial infarction. The purpose of this review is to examine the clinical value of thrombolytic therapy for UA. The multiple lines of evidence supporting intracoronary thrombus formation as a key mechanism in the pathogenesis of UA are reviewed. Studies examining the effect of thrombolytic therapy on angiographic endpoints have shown little effect on the extent of luminal narrowing, but do reveal a decrease in angiographically detected thrombus. Twelve randomized, controlled trials of thrombolytic agents in 611 UA patients with predefined clinical endpoints have been published. These trials varied widely in design and adjunctive therapy both in treated and control grops. Review of these trials show a tendency to fewer clinical events such as death, infarction, and need for revascularization in treated patients, with a corresponding increase in bleeding complications. Clinical efficacy of thrombolytic therapy cannot be excluded by the available data, perhaps in part because of insufficient numbers of patients treated. Determination of the net clinical value of thrombolytic therapy must await larger and more definitive trials.