LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice

Abstract

BackgroundSpecificity 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.Methods and Main FindingsChallenge 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.ConclusionsNF-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.

Ecological Balance of Oral Microbiota Is Required to Maintain Oral Mesenchymal Stem Cell Homeostasis

“…These gene products play vital roles in many physiological processes, in tissue repair and anti‐inflammatory responses. It has been confirmed that Sp1 is a direct target of miR‐21 in human smooth muscle cells and HEK293 cell lines . These findings collectively suggest that Sp1 may be a candidate target gene of miR‐21 in mouse cells.…”

Mutant Glucocorticoid Receptor Binding Elements on the Interleukin-6 Promoter Regulate Dexamethasone Effects

“…Our results revealed that LPS stimulation resulted in the upregulated expressions of in ammatory transcription factors, such as NF-κB [26], AP-1 [27], and Sp1-2 [28]. In addition, LPS increased IL-6 and its promoter activity.…”

Mutant glucocorticoid receptor binding elements on Interleukin-6 promoter regulate dexamethasone effects

“…Our results showed that LPS stimulation resulted in up-regulated expressions of inflammatory transcription factors such as NF-κB [26], AP-1 [27] and Sp1-2 [28].…”

“…Lower shows the promoter activities of mutant GR sites. Among them, mutant GR2 binding site showed a significant decrease compared with other mutant28 binding sites.…”