Up-regulation of <i>fas</i> and <i>fasL</i> pro-apoptotic genes expression in type 1 diabetes patients after autologous haematopoietic stem cell transplantation

Oliveira, Gislane Lelis Vilela de; Malmegrim, K. C. R.; Ferreira, Aline Fernanda; Tognon, Raquel; Kashima, Simone; Couri, Carlos Eduardo Barra; Covas, Dimas Tadeu; Voltarelli, Júlio César; Castro, Fabíola Attié de

doi:10.1111/j.1365-2249.2012.04583.x

Cited by 28 publications

(22 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inducible NO synthase (iNOS) and Fas, important regulators of beta cell apoptosis, are regulated by the noncanonical NF-κB pathway [1,6,38]. Although Fas upregulation is mostly related to cell death in vivo [39,40], decreased iNOS expression and NO production could contribute to the decreased apoptosis in NFκB2-silenced cells [1,6,38]. Importantly, the non-canonical pathway enhances the expression of the chemokines Ccl5, Ccl19 and Cxcl12.…”

Section: Discussionmentioning

confidence: 99%

The non-canonical NF-κB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro

et al. 2015

View full text Add to dashboard Cite

Aims/hypothesis Activation of the transcription factor nuclear factor (NF)-κB by proinflammatory cytokines plays an important role in beta cell demise in type 1 diabetes. Two main signalling pathways are known to activate NF-κB, namely the canonical and the non-canonical pathways. Up to now, studies on the role of NF-κB activation in beta cells have focused on the canonical pathway. The aim of this study was to investigate whether cytokines activate the non-canonical pathway in beta cells, how this pathway is regulated and the consequences of its activation on beta cell fate. Methods NF-κB signalling was analysed by immunoblotting, promoter reporter assays and real-time RT-PCR, after knockdown or overexpression of key genes/proteins. INS-1E cells, FACS-purified rat beta cells and the human beta cell line EndoC-βH1 exposed to cytokines were used as models. Results IL-1β plus IFN-γ induced stabilisation of NF-κB-inducing kinase and increased the expression and cleavage of p100 protein, culminating in the nuclear translocation of p52, the hallmark of the non-canonical signalling. This activation relied on different crosstalks between the canonical and non-canonical pathways, some of which were beta cell specific. Importantly, cytokine-mediated activation of the non-canonical pathway controlled the expression of 'late' NF-κB-dependent genes, regulating both pro-apoptotic and inflammatory responses, which are implicated in beta cell loss in early type 1 diabetes. Conclusions/interpretation The atypical activation of the non-canonical NF-κB pathway by proinflammatory cytokines constitutes a novel 'feed-forward' mechanism that contributes to the particularly pro-apoptotic effect of NF-κB in beta cells.

show abstract

Section: Discussionmentioning

confidence: 99%

The non-canonical NF-κB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Interestingly, further analysis revealed significantly longer survival of the remaining b-cells in those patients with autoantibodies against only one antigen than in those with autoantibodies against two or more antigens, resulting in higher C-peptide levels during follow-up and insulin independence [44]. In a Brazilian cohort of 14 T1D patients, GADA titers were also reduced during post-AHSCT follow-up and correlated with increased C-peptide levels [45], indicating its prognostic value. Although monitoring T-cell specific responses may represent better the autoreactive reactions, no work has yet evaluated the specific islet autoreactive T-cell prognostic value in the AHSCT context for T1D patients.…”

Section: Depletion Of the Autoimmune Repertoirementioning

confidence: 95%

Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases

Arruda

Clave

Douay

et al. 2016

Current Research in Translational Medicine

View full text Add to dashboard Cite

“…These changes are associated with disease remission and are reversed with disease reactivation, indicating persistence of the autoimmune clone [33,34]. De Oliveira and colleagues showed that another effect of "immunologic reset" is up-regulation of fas and fasL proapoptotic genes expression in patients' peripheral blood mononuclear cells after autologous hematopoietic stem cell transplantation [35].…”

Section: Hematopoietic Stem Cell Transplantation For Autoimmune Diseasesmentioning

confidence: 99%

Risks, Benefits, and Therapeutic Potential of Hematopoietic Stem Cell Transplantation for Autoimmune Diabetes

2012

View full text Add to dashboard Cite

Type 1 diabetes mellitus is a chronic disease that results from the autoimmune response against pancreatic insulin producing β cells. Apart of several insulin regimens, since the decade of 80s various immunomodulatory regimens were tested aiming at blocking some steps of the autoimmune process against β cell mass and at promoting β cell preservation. In the last years, some independent research groups tried to cure type 1 diabetes with an "immunologic reset" provided by autologous hematopoietic stem cell transplantation in newly diagnosed patients, and the majority of patients became free form insulin with increasing levels of C-peptide along the time. In this review, we discuss the biology of hematopoietic stem cells and the possible advantages and disadvantages related to the high dose immunosuppression followed by autologous hematopoietic stem cell transplantation.

show abstract

Up-regulation of fas and fasL pro-apoptotic genes expression in type 1 diabetes patients after autologous haematopoietic stem cell transplantation

Cited by 28 publications

References 59 publications

The non-canonical NF-κB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro

The non-canonical NF-κB pathway is induced by cytokines in pancreatic beta cells and contributes to cell death and proinflammatory responses in vitro

Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases

Risks, Benefits, and Therapeutic Potential of Hematopoietic Stem Cell Transplantation for Autoimmune Diabetes

Contact Info

Product

Resources

About