Estrogen-related MxA transcriptional variation in hepatitis C virus-infected patients

Mekky, Radwa Y.; Hamdi, Nabila; El-Akel, Wafaa; Esmat, Gamal; Abdelaziz, Ahmed Ihab

doi:10.1016/j.trsl.2011.08.002

Cited by 13 publications

(14 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pretreatment with E2 significantly downregulated MxA expression in IFN-stimulated PBMCs (Fig. 1), which corroborates our previous findings and demonstrates the suppressive effect that E2 has on the JAK-STAT pathway [6]. Prestimulation with TAM was able to reverse this effect and significantly upregulate MxA expression showing that in PBMCs of HCV-infected females, TAM acts as an ER antagonist to partially alleviate the suppressive effect of E2 on the JAK-STAT pathway (Fig.…”

Section: Discussionsupporting

confidence: 90%

“…In our previous research, premenopausal females, postmenopausal females and males all demonstrated comparable effects upon stimulations with IFN, E2 and ICI 182/780 [6]; therefore, in this study, only premenopausal females were used as the cohort. To study the activation of the JAK‐STAT pathway, PBMCs were stimulated with exogenous IFN and the level of MxA gene induction was observed.…”

Section: Discussionmentioning

confidence: 99%

“…Our research team has recently shown a gender impact on the host genetic response to HCV infection in PBMCs where premenopausal females showed the highest baseline expression of the antiviral interferon (IFN)-stimulated gene (ISG), Myxovirus resistance protein (MxA), when compared to both males and postmenopausal females. Prestimulation of the PBMCs with E2 led to downregulation of MxA expression in all groups, an effect that was reversed by addition of ICI 182/ 780 [6]. The effect of Tamoxifen (TAM) on the host immune response is ambiguous.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tamoxifen alleviates hepatitis C virus‐induced inhibition of both toll‐like receptor 7 and JAK‐STAT signalling pathways in PBMCs of infected Egyptian females

Fawzy

Negm

Ahmed

et al. 2012

Journal of Viral Hepatitis

View full text Add to dashboard Cite

Summary. Hepatitis C virus (HCV) is a major health concern in Egypt being highly prevalent among Egyptians. The two genders experience different responses to HCV infection and show variations in response to interferon (IFN)-based therapy that may be attributed to sex hormones. We previously demonstrated the suppressive effect of 17β-estradiol (E2) on the expression of the IFN-stimulated gene MxA in HCV-infected peripheral blood mononuclear cells (PBMCs). The selective oestrogen receptor (ER) modulator Tamoxifen has been shown to have an antiviral effect against HCV, but its effect on the host immune response is unknown. We investigated the effect of Tamoxifen on the IFN signalling pathways in PBMCs of HCV-infected Egyptian females. We pooled PBMCs and treated then with exogenous interferon alpha (IFNα) or the TLR7 ligand, Imiquimod, and quantified the relative expressions of MxA using RTqPCR. Studies were performed with and without Tamoxifen pretreatment. Pretreatment with Tamoxifen reversed the suppressive effect of E2 on the JAK-STAT pathway in IFNα-treated PBMCs as indicated by a significant increase in MxA expression (P = 0.05*). Tamoxifen pretreatment also significantly upregulated MxA expression in Imiquimod-treated PBMCs (P = 0.0011**), an effect not ascribed to ER blocking nor to an upregulation in TLR7 expression because Tamoxifen showed no potentiating effect on the expression of the receptor. In conclusion, our findings reveal that Tamoxifen has immunomodulatory effects whereby it enhances the host IFN signalling pathways during HCV infection.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tamoxifen alleviates hepatitis C virus‐induced inhibition of both toll‐like receptor 7 and JAK‐STAT signalling pathways in PBMCs of infected Egyptian females

Fawzy

Negm

Ahmed

et al. 2012

Journal of Viral Hepatitis

View full text Add to dashboard Cite

show abstract

“…Gender discrepancies in immune response to HCV infections and during HCV therapy have prompted researchers to investigate the cause of such inconsistencies. Undertaking a broad approach, this research group has investigated the effects of two female sex hormones, E2 and progesterone, providing findings and evidence substantiating the contribution of each of these hormones during immune response to HCV [Fawzy et al, ; Mekky et al, ; Tayel et al, ]. Progesterone was found to have a negative impact on the IFN signaling pathway in PBMCs from patients infected with HCV whereby it suppressed TLR7 expression in both genders and MxA expression in females [Tayel et al, ].…”

Section: Discussionmentioning

confidence: 99%

“…Whereas little evidence substantiates the effects of testosterone on immune response to HCV infection, several studies have documented the effects of the 17β‐estradiol (E2). An association between the gender of the host and their genetic response to HCV infection was revealed whereby peripheral blood mononuclear cells (PBMCs) of premenopausal females expressed the greatest baseline levels of the antiviral interferon (IFN)‐stimulated gene (ISG) Myxovirus resistance protein (MxA) when compared to both males and postmenopausal females; in addition, when cultures of PBMCs were prestimulated with E2, suppression of MxA expression was observed in all groups, an effect that was reversed by addition of the estrogen receptor antagonist ICI 182/780 [Mekky et al, ].…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen downregulates MxA expression by suppressing TLR7 expression in PBMCs of males infected with HCV

Fawzy

Negm

Ahmed

et al. 2014

Journal of Medical Virology

Self Cite

View full text Add to dashboard Cite

Gender discrepancies in immune response to HCV infections and during HCV therapy exist and previous findings including those from this research team indicate the female sex hormone, 17β-estradiol (E2), to be one probable cause of such inconsistencies. Also, it was recently demonstrated that estrogen receptor modulator Tamoxifen (TAM) exerts an upmodulating/enhancing effect on the TLR7 and JAK-STAT pathways in PBMCs of premenopausal females infected with HCV. Pursuing this work, a discrepancy was noticed in the results from male patients, therefore this study aimed to determine whether the effects of TAM previously observed in the PBMCs of women would hold true in PBMCs from males infected with HCV. Isolated PBMCs were pooled and relative expression of the TLR7 was quantified using RTqPCR. Sets of PBMCs were treated with exogenous interferon alpha (IFNα) or the TLR7 ligand, Imiquimod; these stimulations were performed with and without E2 and TAM pretreatment and the relative gene expressions of TLR7 and MxA were measured. Pretreatment with E2 and IFNα downregulated TLR7 (**P = 0.0080) and TAM further decreased this expression significantly (*P = 0.0284). TAM pretreatment also caused a significant downregulation in MxA expression in Imiquimod-stimulated PBMCs (*P = 0.0218). In conclusion, TAM displays several paradoxical effects in PBMCs of males infected with HCV compared to those of females. Contrary to the previous study involving premenopausal females, in PBMCs of infected males TAM may decrease IFNα release as indicated by reduced MxA expression possibly via the suppression of TLR7 expression.

show abstract

Reply

Ryan

Altamura²,

Muckenthaler³

et al. 2014

Hepatology

View full text Add to dashboard Cite

Estrogen-related MxA transcriptional variation in hepatitis C virus-infected patients

Cited by 13 publications

References 18 publications

Tamoxifen alleviates hepatitis C virus‐induced inhibition of both toll‐like receptor 7 and JAK‐STAT signalling pathways in PBMCs of infected Egyptian females

Tamoxifen alleviates hepatitis C virus‐induced inhibition of both toll‐like receptor 7 and JAK‐STAT signalling pathways in PBMCs of infected Egyptian females

Tamoxifen downregulates MxA expression by suppressing TLR7 expression in PBMCs of males infected with HCV

Reply

Contact Info

Product

Resources

About