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Role of nuclear factor kappaB in ovarian hormone-mediated stress hypersensitivity in female mice.

ABSTRACT: The molecular mechanisms of stress-induced depressive behaviors have been characterized extensively in male rodents; however, much less is known about female subjects, despite the fact that human depression is far more prevalent in women.To gain insight into these mechanisms, we performed microarray analysis in nucleus accumbens (NAc), a key brain reward region implicated in depression, in ovariectomized (OVX) and gonadally intact female mice after chronic unpredictable stress and measured stress-induced depression-like behavior in the forced swim test (FST). Male mice were studied in the FST for comparison.We find that stress regulation of genes in NAc of gonadally intact female mice is blunted in OVX mice. This pattern of gene regulation is consistent with behavioral findings on the FST: the pro-depression-like effect of stress in intact female mice is absent in OVX female and gonadally intact male mice. We identified, among many genes regulated by stress, several nuclear factor kappaB (NFkappaB) subunits-a pro-survival transcription factor involved in cellular responses to stress-as being highly upregulated in NAc of OVX mice. Given the role of NFkappaB during stress, we hypothesized that upregulation of NFkappaB by OVX decreases susceptibility to stress. Indeed, we show that inhibition of NFkappaB in NAc of OVX animals increases susceptibility to stress-induced depressive behaviors, whereas activation of NFkappaB in NAc of intact female subjects blocks susceptibility.These results suggest a hormonal mechanism of NFkappaB regulation that contributes to stress-induced depressive behaviors in female subjects and might represent a mechanism for gender differences in prevalence rates of these disorders in humans.

SUBMITTER: LaPlant Q

PROVIDER: S-EPMC2746634 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Role of nuclear factor kappaB in ovarian hormone-mediated stress hypersensitivity in female mice.

LaPlant Quincey Q Chakravarty Sumana S Vialou Vincent V Mukherjee Shibani S Koo Ja Wook JW Kalahasti Geetha G Bradbury Kathryn R KR Taylor Shameeke V SV Maze Ian I Kumar Arvind A Graham Ami A Birnbaum Shari G SG Krishnan Vaishnav V Truong Hoang-Trang HT Neve Rachael L RL Nestler Eric J EJ Russo Scott J SJ

Biological psychiatry 20090228 10

<h4>Background</h4>The molecular mechanisms of stress-induced depressive behaviors have been characterized extensively in male rodents; however, much less is known about female subjects, despite the fact that human depression is far more prevalent in women.<h4>Methods</h4>To gain insight into these mechanisms, we performed microarray analysis in nucleus accumbens (NAc), a key brain reward region implicated in depression, in ovariectomized (OVX) and gonadally intact female mice after chronic unpr ...[more]

PMID: 19251249

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Project description:BackgroundAdipocytes express inflammatory mediators that contribute to the low-level, chronic inflammation found in obese subjects and have been linked to the onset of cardiovascular disorders and insulin resistance associated with type 2 diabetes mellitus. A reduction in inflammatory gene expression in adipocytes would be expected to reverse this low-level, inflammatory state and improve cardiovascular function and insulin sensitivity. The natural products, curcumin and resveratrol, are established anti-inflammatory compounds that mediate their effects by inhibiting activation of NF-kappaB signaling. In the present study, we examined if these natural products can inhibit NF-kappaB activation in adipocytes and in doing so reduce cytokine expression.MethodsCytokine (TNF-alpha, IL-1beta, IL-6) and COX-2 gene expression in 3T3-L1-derived adipocytes was measured by quantitative real-time PCR (qRT-PCR) with or without TNFalpha-stimulation. Cytokine protein and prostaglandin E2 (PGE2) expression were measured by ELISA. Effects of curcumin and resveratrol were evaluated by treating TNFalpha-stimulated adipocytes with each compound and 1) assessing the activation state of the NF-kappaB signaling pathway and 2) measuring inflammatory gene expression by qRT-PCR and ELISA.ResultsBoth preadipocytes and differentiated adipocytes express the genes for TNF-alpha, IL-6, and COX-2, key mediators of the inflammatory response. Preadipocytes were also found to express IL-1beta; however, IL-1beta expression was absent in differentiated adipocytes. TNF-alpha treatment activated NF-kappaB signaling in differentiated adipocytes by inducing IkappaB degradation and NF-kappaB translocation to the nucleus, and as a result increased IL-6 (6-fold) and COX-2 (2.5-fold) mRNA levels. TNF-alpha also activated IL-1beta gene expression in differentiated adipocytes, but had no effect on endogenous TNF-alpha mRNA levels. No detectable TNFalpha or IL-1beta was secreted by adipocytes. Curcumin and resveratrol treatment inhibited NF-kappaB activation and resulted in a reduction of TNF-alpha, IL-1beta, IL-6, and COX-2 gene expression (IC50 = 2 muM) and a reduction of secreted IL-6 and PGE2 (IC50 ~ 20 muM).ConclusionCurcumin and resveratrol are able to inhibit TNFalpha-activated NF-kappaB signaling in adipocytes and as a result significantly reduce cytokine expression. These data suggest that curcumin and resveratrol may provide a novel and safe approach to reduce or inhibit the chronic inflammatory properties of adipose tissue.

Project description:Activation of transforming growth factor-beta (TGF-beta) and activin receptors leads to phosphorylation of Sma- and Mad-related protein 2 (Smad2) and Smad3, which function as transcription factors to regulate gene expression. Smad7 is a regulatory protein which is able to inhibit TGF-beta and activin signalling in a negative-feedback loop, mediated by a direct regulation by Smad3 and Smad4 via a Smad-binding element (SBE) in the Smad7 promoter. Interestingly, we found that the Smad7 promoter was also regulated by nuclear factor kappaB (NF-kappaB), a transcription factor which plays an important role in inflammation and the immune response. Expression of NF-kappaB p65 subunit was able to inhibit the Smad7 promoter activity, and this inhibition could be reversed by co-expression of IkappaB, an inhibitor of NF-kappaB. In addition, the inhibitory activity of p65 was observed in a minimal promoter that contained only the Smad7 SBE and a TATA box, without any consensus NF-kappaB binding site. This inhibitory effect appeared to be common to other TGF-beta- and activin-responsive promoters, since p65 also inhibited the forkhead-activin-signal-transducer-2-mediated activation of a Xenopus Mix.2 promoter, as well as the Smad3-mediated activation of 3TP-lux which contains PMA-responsive elements and a plasminogen-activator-inhibitor-1 promoter. Activation of endogenous NF-kappaB by tumour necrosis factor-alpha (TNF-alpha) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells. In human hepatoma HepG2 cells, TNF-alpha was able to inhibit TGF-beta- and activin-mediated transcriptional activation. Furthermore, overexpression of the transcription co-activator p300 could abrogate the inhibitory effect of NF-kappaB on the Smad7 promoter. Taken together, these data have indicated a novel mode of crosstalk between the Smad and the NF-kappaB signalling cascades at the transcriptional level by competing for a limiting pool of transcription co-activators.

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Role of nuclear factor kappaB in ovarian hormone-mediated stress hypersensitivity in female mice.

Publications

Role of nuclear factor kappaB in ovarian hormone-mediated stress hypersensitivity in female mice.

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