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Estrogen modulates NF?B signaling by enhancing I?B? levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor-?.

ABSTRACT:

Background

NF?B signaling is critical for expression of genes involved in the vascular injury response. We have shown that estrogen (17?-estradiol, E2) inhibits expression of these genes in an estrogen receptor (ER)-dependent manner in injured rat carotid arteries and in tumor necrosis factor (TNF)-? treated rat aortic smooth muscle cells (RASMCs). This study tested whether E2 inhibits NF?B signaling in RASMCs and defined the mechanisms.

Methodology/principal findings

TNF-? treated RASMCs demonstrated rapid degradation of I?B? (10-30 min), followed by dramatic increases in I?B? mRNA and protein synthesis (40-60 min). E2 enhanced TNF-? induced I?B? synthesis without affecting I?B? degradation. Chromatin immunoprecipitation (ChIP) assays revealed that E2 pretreatment both enhanced TNF-? induced binding of NF?B p65 to the I?B? promoter and suppressed TNF-? induced binding of NF?B p65 to and reduced the levels of acetylated histone 3 at promoters of monocyte chemotactic protein (MCP)-1 and cytokine-induced neutrophil chemoattractant (CINC)-2? genes. ChIP analyses also demonstrated that ER? can be recruited to the promoters of MCP-1 and CINC-2? during co-treatment with TNF-? and E2.

Conclusions

These data demonstrate that E2 inhibits inflammation in RASMCs by two distinct mechanisms: promoting new synthesis of I?B?, thus accelerating a negative feedback loop in NF?B signaling, and directly inhibiting binding of NF?B to the promoters of inflammatory genes. This first demonstration of multifaceted modulation of NF?B signaling by E2 may represent a novel mechanism by which E2 protects the vasculature against inflammatory injury.

SUBMITTER: Xing D

PROVIDER: S-EPMC3378567 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Estrogen modulates NFκB signaling by enhancing IκBα levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor-β.

Xing Dongqi D Oparil Suzanne S Yu Hao H Gong Kaizheng K Feng Wenguang W Black Jonathan J Chen Yiu-Fai YF Nozell Susan S

PloS one 20120619 6

<h4>Background</h4>NFκB signaling is critical for expression of genes involved in the vascular injury response. We have shown that estrogen (17β-estradiol, E2) inhibits expression of these genes in an estrogen receptor (ER)-dependent manner in injured rat carotid arteries and in tumor necrosis factor (TNF)-α treated rat aortic smooth muscle cells (RASMCs). This study tested whether E2 inhibits NFκB signaling in RASMCs and defined the mechanisms.<h4>Methodology/principal findings</h4>TNF-α treate ...[more]

PMID: 22723832

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