Inhibition of Nuclear Factor-Kappa B Sensitises Anterior Pituitary Cells to Tumour Necrosis Factor-α- and Lipopolysaccharide-Induced Apoptosis

Eijo, Guadalupe; Zárate, Sandra; Jaita, Gabriela; Ferraris, Jimena; Magri, María Laura; Zaldivar, V.; Radl, Daniela; Boti, Valeria; Pisera, Daniel; Seilicovich, Adriana

doi:10.1111/j.1365-2826.2011.02157.x

Cited by 10 publications

(11 citation statements)

References 47 publications

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“…In normal pituitary cells, oestrogens inhibit the NF‐κB pathway, probably by controlling NF‐κB intracellular localisation as reported for other cell types . Indeed, we previously reported that ER activation blocks LPS‐ and TNF‐α‐induced nuclear translocation of NF‐κB/p65 and p50 . In the present study, we found that oestrogens have the opposite effect in GH3 cells because they increased nuclear levels of NF‐κB/105, p65 and p50.…”

Section: Discussionsupporting

confidence: 83%

“…We previously reported that, in normal anterior pituitary cells, E 2 decreases TNF‐α‐induced NF‐κB nuclear translocation and reduces Bcl‐xL expression, an anti‐apoptotic protein target for this transcriptional factor . To evaluate whether oestrogens also modulate NF‐κB activity in pituitary tumour cells, we examined the effect of E 2 on basal and TNF‐α‐induced nuclear translocation of NF‐κB and on Bcl‐xL expression in GH3 pituitary tumour cells.…”

Section: Resultsmentioning

confidence: 99%

“…The nuclear fraction was obtained from rat anterior pituitary cells or GH3 cells using fresh lysis buffer containing10 m m KCl, 2 m m MgCl 2 , 0.5 m m dithiothreitol, 1% IGEPAL, 0.2 m m EDTA in 10 m m Hepes, pH 7.9 and protease inhibitor cocktail (dilution 1 : 100). Following differential centrifugation as described previously , the supernatant was used for the NF‐κB immunoblot assay. The protein concentration of each sample was determined by the Bradford protein assay (Bio‐Rad, Hercules, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Lack of Oestrogenic Inhibition of the Nuclear Factor‐κB Pathway in Somatolactotroph Tumour Cells

Eijo

Gottardo

Jaita

et al. 2015

J Neuroendocrinology

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Activation of nuclear factor (NF)-κB promotes cell proliferation and inhibits apoptosis. We have previously shown that oestrogens sensitise normal anterior pituitary cells to the apoptotic effect of tumour necrosis factor (TNF)-α by inhibiting NF-κB nuclear translocation. In the present study, we examined whether oestrogens also modulate the NF-κB signalling pathway and apoptosis in GH3 cells, a rat somatolactotroph tumour cell line. As determined by Western blotting, 17β-oestradiol (E2 ) (10(-9) m) increased the nuclear concentration of NF-κB/p105, p65 and p50 in GH3 cells. However, E2 did not modify the expression of Bcl-xL, a NF-κB target gene. TNF-α induced apoptosis of GH3 cells incubated in either the presence or absence of E2 . Inhibition of the NF-kB pathway using BAY 11-7082 (BAY) (5 μm) decreased the viability of GH3 cells and increased the percentage of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive GH3 cells. BAY also increased TNF-α-induced apoptosis of GH3 cells, an effect that was further increased by an inhibitor of the c-Jun N-terminal protein kinase pathway, SP600125 (10 μm). We also analysed the role of the NF-κB signalling pathway on proliferation and apoptosis of GH3 tumours in vivo. The administration of BAY to nude mice bearing GH3 tumours increased the number of TUNEL-positive cells and decreased the number of proliferating GH3 cells. These findings suggest that GH3 cells lose their oestrogenic inhibitory action on the NF-κB pathway and that the pro-apoptotic effect of TNF-α on these tumour pituitary cells does not require sensitisation by oestrogens as occurs in normal pituitary cells. NF-κB was required for the survival of GH3 cells, suggesting that pharmacological inhibition of the NF-κB pathway could interfere with pituitary tumour progression.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Lack of Oestrogenic Inhibition of the Nuclear Factor‐κB Pathway in Somatolactotroph Tumour Cells

Eijo

Gottardo

Jaita

et al. 2015

J Neuroendocrinology

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“…In vitro studies showed that pre-treatment with oestradiol was able to prevent neuronal death by inhibiting the activation of p38 MAPK after the treatment of cells with Aβ (Valles et al 2008). Eijo et al (2011) described that oestradiol was able to decrease TNFα-induced, NFκB p65 and p50 nuclear translocation in primary cultures of anterior pituitary cells from ovariectomized rats. Inhibition of NFκB by melatonin has been also previously reported in other experimental models that showed how melatonin prevented NFκB activation by oxidative stress (Veneroso et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

Kireev

Vara

Viña

et al. 2014

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The aim of this study was to determine the outcomes of oestrogen and melatonin treatments following long-term ovarian hormone depletion on neuroinflammation and apoptotic processes in dentate gyrus of hippocampi. Forty-six female Wistar rats of 22 months of age were used. Twelve of them remained intact, and the other 34 were ovariectomized at 12 months of age. Ovariectomized animals were divided into three groups and treated for 10 weeks with oestrogens, melatonin or saline. All rats were killed by decapitation at 24 months of age, and dentate gyri were collected. A group of 2 month-old intact female rats was used as young control. The levels of pro-inflammatory cytokines and heat shock protein 70 (HSP 70) were analysed by ELISA. The expressions of TNFα, IL1β, GFAP, nNOS, iNOS, HO-1, NFκB, Bax, Bad, AIF, Bcl2 and SIRT1 genes were detected by real-time (RT)-PCR. Western blots were used to measure the protein expression of NFκB p65, NFκB p50/105, IκBα, IκBβ, p38 MAPK, MAP-2 and synapsin I. We have assessed the ability of 17β-oestradiol and melatonin administration to downregulate markers of neuroinflammation in the dentate gyrus of ovariectomized female rats. Results indicated that 17β-oestradiol and melatonin treatments were able to significantly decrease expression of pro-inflammatory cytokines, iNOS and HO-1 in the hippocampus when compared to non-treated animals. A similar age-and long-term ovarian hormone depletion-related increase in GFAP was also attenuated after both melatonin and oestradiol treatments. In a similar way to oestradiol, melatonin decreased the activation of p38 MAPK and NFκB pathways. The treatments enhanced the levels of synaptic molecules synapsin I and MAP-2 and have been shown to modulate the pro-antiapoptotic ratio favouring the second and to increase SIRT1 expression. These findings support the potential therapeutic role of melatonin and oestradiol as protective antiinflammatory agents for the central nervous system during menopause.

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“…Hence, to elucidate whether PRL proapoptotic effect requires STAT5 regulation of Bcl-2 family proteins, we determined the level of expression of two members of this family that we have previously shown to be regulators of anterior pituitary cells apoptosis, i.e. antiapoptotic Bcl-2 and proapoptotic Bax [28, 49, 50]. PRLR antagonist decreased Bax and increased Bcl-2 expression levels, further supporting the idea that PRLR activation promotes a proapoptotic phenotype in GH3 cells.…”

Section: Discussionmentioning

confidence: 99%

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

et al. 2018

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Prolactinomas are increasingly viewed as a “problem of signal transduction.” Consequently, the identification of factors and signaling pathways that control lactotrope cell turnover is needed in order to encourage new therapeutic developments. We have previously shown that prolactin (PRL) acts as a proapoptotic and antiproliferative factor on lactotropes, maintaining anterior pituitary cell homeostasis, which contrasts with the classical antiapoptotic and/or proliferative actions exerted by PRL in most other target tissues. We aimed to investigate the PRLR-triggered signaling pathways mediating these nonclassical effects of PRL in the pituitary. Our results suggest that (i) the PRLR/Jak2/STAT5 pathway is constitutively active in GH3 cells and contributes to PRL-induced apoptosis by increasing the Bax/Bcl-2 ratio, (ii) PRL inhibits ERK1/2 and Akt phosphorylation, thereby contributing to its proapoptotic effect, and (iii) the PI3K/Akt pathway participates in the PRL-mediated control of lactotrope proliferation. We hypothesize that the alteration of PRL actions in lactotrope homeostasis due to the dysregulation of any of the mechanisms of actions described above may contribute to the pathogenesis of prolactinomas.

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Inhibition of Nuclear Factor-Kappa B Sensitises Anterior Pituitary Cells to Tumour Necrosis Factor-α- and Lipopolysaccharide-Induced Apoptosis

Cited by 10 publications

References 47 publications

Lack of Oestrogenic Inhibition of the Nuclear Factor‐κB Pathway in Somatolactotroph Tumour Cells

Lack of Oestrogenic Inhibition of the Nuclear Factor‐κB Pathway in Somatolactotroph Tumour Cells

Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

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