@entity558 Down-Regulates Specificity Protein 1 Activity by Activating NF-kB Pathway in Endotoxemic XXXX .

@entity19 @entity558 @entity10591 @entity1618
BACKGROUND: @entity10591 mediates the transcription of a large number of constitutive genes encoding physiological mediators. NF-kB mediates the expression of hundreds of inducible genes encoding pathological mediators. Crosstalk between @entity10591 and NF-kB pathways could be pathophysiologically significant, but has not been studied. This study examined the crosstalk between the two pathways and defined the role of NF-kB signaling in @entity558 -induced down-regulation of @entity10591 activity. METHODS AND MAIN FINDINGS: Challenge of wild type @entity19 with samonelia enteritidis @entity558 (10 mg/kg, i.p.) down-regulated @entity10591 binding activity in lungs in a time-dependent manner, which was concomitantly associated with an increased NF-kB activity. @entity558 down-regulates @entity10591 activity by inducing an @entity558 inducible @entity10591 -degrading enzyme (LISPDE) activity, which selectively degrades @entity10591 protein, resulting in @entity10591 down-regulation. Blockade of NF-kB activation in @entity19 deficient in NF-kB p50 gene (NF-kB-KO) suppressed LISPDE activity, prevented @entity10591 protein degradation, and reversed the down-regulation of @entity10591 DNA binding activity and eNOS expression (an indicator of @entity10591 transactivation activity). Inhibition of LISPDE activity using a selective LISPDE inhibitor mimicked the effects of NF-kB blockade. Pretreatment of @entity558 -challenged WT @entity19 with a selective LISPDE inhibitor increased nuclear @entity10591 protein content, restored @entity10591 DNA binding activity and reversed eNOS protein down-regulation in lungs. Enhancing tissue level of @entity10591 activity by inhibiting NF-kB-mediated @entity10591 down-regulation increased tissue level of @entity1618 and decreased tissue level of TNF- ain the lungs. CONCLUSIONS: NF-kB signaling mediates @entity558 -induced down-regulation of @entity10591 activity. Activation of NF-kB pathway suppresses @entity10591 activity and @entity10591 -mediated anti-inflammatory signals. Conversely, @entity10591 signaling counter-regulates NF-kB-mediated inflammatory response. Crosstalk between NF-kB and @entity10591 pathways regulates the balance between pro- and anti-inflammatory cytokines.
