SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production

Jauharoh, Siti Nur Aisyah; Saegusa, Jun; Sugimoto, Tsuneaki; Ardianto, Bambang; Kasagi, Shimpei; Sugiyama, Daisuke; Kurimoto, Chiyo; Tokuno, Osamu; Nakamachi, Yuji; Kumagai, Shunichi; Kawano, Seiji

doi:10.1016/j.bbrc.2011.12.010

Cited by 45 publications

(39 citation statements)

References 25 publications

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“…In order to explore potential underlying mechanisms through which reduced IFNα transcript levels in MSG tissues derived from SS patients complicated by lymphoma could predispose to malignant transformation in the setting of SS, we further measured transcript levels of previously reported IFNα related apoptotic molecules including TRAIL [35, 36]; p53, an intrinsic apoptotic inducer and gatekeeper of cancer development; and Ro52/TRIM21 -an IFNα induced, SS related, E3 ubiquitin ligase with a prominent regulatory role in inflammation as well as with anti-proliferative and pro-apoptotic properties [37, 38]. A strong positive correlation of IFNα mRNA levels with TRAIL, p53 and Ro52/TRIM21 mRNA levels (r=0.53/p:0.02, r=0.55/p:0.02 and r=0.71/p:0.0002, respectively) was detected, indicating that low IFNα levels might be related to lower expression of apoptotic/antitumor genes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…IFNα has been widely used as an antineoplastic agent [45], mainly through pro-apoptotic effects on several tumor cells, including myeloma, glioma and melanoma cells [46], and potentiation of natural killer (NK) cell cytotoxicity through induction of the Fas/FasL pathway [47]. The tumor suppressor gene p53 [36], the extrinsic apoptotic molecule TRAIL [35] and the Ro52 autoantigen –a major SS autoantigen known to negatively regulate the anti-apoptotic protein Bcl-2- [38] have been previously shown to be induced by IFNα, possibly accounting for its antiproliferative properties. In line with these observations, IFNα transcript levels at the level of SS MSG tissues in our study were strongly correlated with mRNA expression of pro-apoptotic molecules TRAIL, p53 and Ro52, indicating suppressed IFNα as an important contributor to the survival of malignant B-cell populations in the setting of SS.…”

Section: Discussionmentioning

confidence: 99%

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Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

Nezos

Gravani

Tassidou

et al. 2015

Journal of Autoimmunity

212

181

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Both type I and II interferons (IFNs) have been implicated in the pathogenesis of Sjogren's syndrome (SS). We aimed to explore the contribution of type I and II IFN signatures in the generation of distinct SS clinical phenotypes including lymphoma development. Peripheral blood (PB) from SS patients (n=31), SS patients complicated by lymphoma (n=13) and healthy controls (HC, n=30) were subjected to real-time PCR for 3 interferon inducible genes (IFIGs) preferentially induced by type I IFN, 2 IFIGs preferentially induced by IFNγ as well as for IFNα and IFNγ genes. The same analysis was performed in minor salivary gland tissues (MSG) derived from 31 SS patients, 10 SS-lymphoma patients and 17 sicca controls (SC). In PB and MSG tissues, overexpression of both type I and type II IFIGs was observed in SS patients versus HC and SC, respectively, with a predominance of type I IFN signature in PB and a type II IFN signature in MSG tissues. In SS-lymphoma MSG tissues, lower IFNα, but higher IFNγ and type II IFIG transcripts compared to both SS and SC were observed. In receiver operating characteristic curve analysis, IFNγ/IFNα mRNA ratio in MSG tissues showed the best discrimination for lymphoma development. Discrete expression patterns of type I and II IFN signatures might be related to distinct SS clinical phenotypes. Additionally, IFNγ/IFNα mRNA ratio in diagnostic salivary gland biopsies is proposed as a novel histopathological biomarker for the prediction of in situ lymphoma development in the setting of SS.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

Nezos

Gravani

Tassidou

et al. 2015

Journal of Autoimmunity

212

181

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show abstract

“…Recent reports have noted that H 2 O 2 treatment of cell lines increases 52-kDa SSA protein levels in the cytoplasm and subsequently elicits translocation of the SSA protein to the nuclei [75]. This SSA protein accumulated in the nuclei downregulates Bcl-2 expression and thus provokes apoptosis [76]. These results suggest that the 52-kDa SSA functions as a proapoptotic molecule.…”

Section: Discussionmentioning

confidence: 92%

“…Additionally, our study suggested that expression of autoantigens was positively correlated with expression of both thymidine glycol and ssDNA, and their rank correlation coefficients were significant. As mentioned above, SSA and Ifi202 may serve as apoptotic promoters [76,78]. Taken together, the downregulated expression of autoantigens by EGCG administration may contribute to the inhibitory effects on ROSmediated sequential pathogenetic cycle including DNA damage and p53-dependent apoptosis, which function in a more organ-specific rather than systemic manner.…”

Section: Discussionmentioning

confidence: 98%

Epigallocatechin gallate inhibits oxidative stress-induced DNA damage and apoptosis in MRL-Fas^lprmice with autoimmune sialadenitis via upregulation of heme oxygenase-1 and Bcl-2

et al. 2014

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Pathogenic effects of reactive oxygen species (ROS) in the salivary glands of patients with Sjögren's syndrome have been demonstrated. Epigallocatechin gallate (EGCG), which is a catechin derivative and exhibits potent antioxidant activity, has been reported to ameliorate autoimmune sialadenitis in a murine model, but the mechanism underlying its protective action remains to be investigated. Herein, we examined the effects of EGCG administration to MRL/MpJ-lpr/lpr (MRL-Fas(lpr)) mice on disease severity of autoimmune sialadenitis and protein expression levels of 11 sialadenitis-related molecules - heme oxygenase-1 (HO-1) (antioxidant); thymidine glycol (marker of DNA damage); gp91phox/NADPH oxidase 2 (prooxidant); single-stranded DNA (ssDNA) and cleaved caspase 3 (apoptotic cell markers); p53 and Bax (proapoptotic molecules); Bcl-2 (antiapoptotic molecule); SSA/Ro, SSB/La, and Ifi202 (autoantigens). In EGCG-treated mice, the severity of sialadenitis was substantially decreased. Expression levels of thymidine glycol, gp91phox, ssDNA, cleaved caspase 3, p53, Bax, SSA/Ro, SSB/La, and Ifi202 in duct epithelial cells of salivary glands from EGCG-treated mice were reduced, whereas HO-1 and Bcl-2 were overexpressed. Results of correlation analysis among sialadenitis severity and 11 sialadenitis related-molecules, and those of partial correlation analysis between apoptotic related-molecules and sialadenitis severity or HO-1 suggested that the consecutive pathogenic cycle including activated autoimmune reactions, ROS synthesis, DNA damage and p53-dependent apoptosis was associated with the pathogenesis of autoimmune sialadenitis in MRL-Fas(lpr) mice. Overexpression of HO-1 and Bcl-2 mediated by EGCG blocked this pathogenic cycle, subsequently resulting in the inhibition of ROS-mediated DNA damage and apoptosis, and protected salivary gland tissues from oxidative stress. Clinically, green tea catechin may have therapeutic efficacy for Sjögren's syndrome.

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“…Ro-52 also causes increased apoptosis by inhibiting bcl2 production [57,58]. During apoptosis, autoantigens, including Ro-52, are transferred onto the surface of apoptotic blebs where these autoantigens may interact with the immune system in a way that leads to activation and eventually autoantibody formation.…”

Section: Introductionmentioning

confidence: 99%

Update on Pathogenesis of Sjogren's Syndrome

Sandhya¹,

Kurien²,

Danda³

et al. 2017

CRR

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Sjögren’s syndrome is a common autoimmune disease that presents with sicca symptoms and extraglandular features. Sjögren’s syndrome is presumably as common as RA; yet it is poorly understood, underdiagnosed and undertreated. From the usual identity as an autoimmune exocrinopathy to its most recent designate as an autoimmune epithelitis – the journey of SS is complex. We herein review some of the most important milestones that have shed light on different aspects of pathogenesis of this enigmatic disease. This includes role of salivary gland epithelial cells, and their interaction with cells of innate and adaptive immune system. Non-immune factors acting in concert or in parallel with immune factors may also be important. The risk genes identified so far have only weak association, nevertheless advances in genetics have enhanced understanding of disease mechanisms. Role of epigenetic and environmental factors are also being explored. SS also has some unique features such as congenital heart block and high incidence of lymphoma; disease mechanisms accounting for these manifestations are also reviewed.

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SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production

Cited by 45 publications

References 25 publications

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

Epigallocatechin gallate inhibits oxidative stress-induced DNA damage and apoptosis in MRL-Fas^lprmice with autoimmune sialadenitis via upregulation of heme oxygenase-1 and Bcl-2

Update on Pathogenesis of Sjogren's Syndrome

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SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production

Cited by 45 publications

References 25 publications

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

Epigallocatechin gallate inhibits oxidative stress-induced DNA damage and apoptosis in MRL-Faslprmice with autoimmune sialadenitis via upregulation of heme oxygenase-1 and Bcl-2

Update on Pathogenesis of Sjogren's Syndrome

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Product

Resources

About

Epigallocatechin gallate inhibits oxidative stress-induced DNA damage and apoptosis in MRL-Fas^lprmice with autoimmune sialadenitis via upregulation of heme oxygenase-1 and Bcl-2