title: LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice.
abstract: BACKGROUND
  Specificity protein (Sp) 1 mediates the transcription of a large number of constitutive genes encoding physiological mediators. NF-κB mediates the expression of hundreds of inducible genes encoding pathological mediators. Crosstalk between Sp1 and NF-κB 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-κB signaling in LPS-induced down-regulation of Sp1 activity.
  
  
  RESULTS
  Challenge of wild type mice with samonelia enteritidis LPS (10 mg/kg, i.p.) down-regulated Sp1 binding activity in lungs in a time-dependent manner, which was concomitantly associated with an increased NF-κB activity. LPS down-regulates Sp1 activity by inducing an LPS inducible Sp1-degrading enzyme (LISPDE) activity, which selectively degrades Sp1 protein, resulting in Sp1 down-regulation. Blockade of NF-κB activation in mice deficient in NF-κB p50 gene (NF-κB-KO) suppressed LISPDE activity, prevented Sp1 protein degradation, and reversed the down-regulation of Sp1 DNA binding activity and eNOS expression (an indicator of Sp1 transactivation activity). Inhibition of LISPDE activity using a selective LISPDE inhibitor mimicked the effects of NF-κB blockade. Pretreatment of LPS-challenged WT mice with a selective LISPDE inhibitor increased nuclear Sp1 protein content, restored Sp1 DNA binding activity and reversed eNOS protein down-regulation in lungs. Enhancing tissue level of Sp1 activity by inhibiting NF-κB-mediated Sp1 down-regulation increased tissue level of IL-10 and decreased tissue level of TNF- αin the lungs.
  
  
  CONCLUSIONS
  NF-κB signaling mediates LPS-induced down-regulation of Sp1 activity. Activation of NF-κB pathway suppresses Sp1 activity and Sp1-mediated anti-inflammatory signals. Conversely, Sp1 signaling counter-regulates NF-κB-mediated inflammatory response. Crosstalk between NF-κB and Sp1 pathways regulates the balance between pro- and anti-inflammatory cytokines.
authors.affiliation: Centers for Heart and Lung Research, and Pulmonary and Critical Care Medicine, the Feinstein Institute for Medical Research, Manhasset, New York, United States.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Ye
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Hypoxia Medicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Gong
authors.affiliation: Centers for Heart and Lung Research, and Pulmonary and Critical Care Medicine, the Feinstein Institute for Medical Research, Manhasset, New York, United States; Institute of Hypoxia Medicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Shu Fang
authors.initials: SF
authors.lastname: Liu
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D019446:Endotoxemia / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016329:Sp1 Transcription Factor