LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice.
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 signifi...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4478004?pdf=render |
| _version_ | 1819072426523230208 |
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| author | Xiaobing Ye Hong Liu Yong-Sheng Gong Shu Fang Liu |
| author_facet | Xiaobing Ye Hong Liu Yong-Sheng Gong Shu Fang Liu |
| author_sort | Xiaobing Ye |
| collection | DOAJ |
| description | 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.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.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. |
| first_indexed | 2024-12-21T17:37:32Z |
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| id | doaj.art-ae8aa087a6024057885a90924fe334fa |
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| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T17:37:32Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj.art-ae8aa087a6024057885a90924fe334fa2022-12-21T18:55:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01106e013031710.1371/journal.pone.0130317LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice.Xiaobing YeHong LiuYong-Sheng GongShu Fang LiuSpecificity 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.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.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.http://europepmc.org/articles/PMC4478004?pdf=render |
| spellingShingle | Xiaobing Ye Hong Liu Yong-Sheng Gong Shu Fang Liu LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice. PLoS ONE |
| title | LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice. |
| title_full | LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice. |
| title_fullStr | LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice. |
| title_full_unstemmed | LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice. |
| title_short | LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-κB Pathway in Endotoxemic Mice. |
| title_sort | lps down regulates specificity protein 1 activity by activating nf κb pathway in endotoxemic mice |
| url | http://europepmc.org/articles/PMC4478004?pdf=render |
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