Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes

Pirot, Pierre; Cardozo, Alessandra K; Eizirik, Décio L.

doi:10.1590/s0004-27302008000200003

Cited by 132 publications

(123 citation statements)

References 61 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…These cytokines activate the transcription factors nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB) and signal transducers and activators of transcription-1 (STAT-1), respectively [3]. By promoting the production of chemo/cytokines and chemo/cytokine receptors, these factors play a crucial role in the innate as well as the specific immune system [4]. This means that NF-κB and STAT-1, by controlling inflammation and immunity, are possible key factors in the destruction of -cells [5].…”

Section: Introductionmentioning

confidence: 99%

Cytokine-induced human islet cell death in vitro correlates with a persistently high phosphorylation of STAT-1, but not with NF-κB activation

Hindlycke

Lü

Welsh

2012

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

"Cytokine-induced human islet cell death in vitro correlateswith a persistently high phosphorylation of STAT-1, but not with Access to the published version may require subscription. ABSTRACTStudies of insulin producing -cells have reported conflicting responses to NF-κB activation, encompassing both pro-and anti-apoptotic effects, possibly reflecting the use of -cells from different species. Therefore, the aim of this study was to compare the temporal activation of NF-κB in rat and human insulin producing cells and relate this to the dynamics of cell death, STAT-1 activation and the production of nitric oxide (NO). Rat RIN5AH and human islet cells were exposed to the cytokines IL-1 and IFN- and the NOS inhibitor aminoguanidine. Cell death, NO production,  phosphorylation, p65 methylation, STAT-1 phosphorylation and cIAP-2 levels were analyzed at different time-points. Cytokine-induced RIN5AH cell death occurred on day 1, and this was paralleled by NF-B activation, STAT-1 phosphorylation and production of NO. On the other hand, the human islet cells instead died by an NO-independent mechanism on day 3and 5. This later occurring cell death was associated with a gradual decrease in  phosphorylation and p65 methylation, and a lowered expression of the NF-B target genes  and cIAP-2. STAT-1 phosphorylation was persistently high during the entire cytokine exposure period in human islet cells. The results favor a pro-survival role of NF-B and a pro-apoptotic role of STAT-1 in human islet cells. Thus, rodent insulin producing cells may not be suitable as models for human -cells in the context of cytokine-induced damage.

show abstract

Section: Introductionmentioning

confidence: 99%

Cytokine-induced human islet cell death in vitro correlates with a persistently high phosphorylation of STAT-1, but not with NF-κB activation

Hindlycke

Lü

Welsh

2012

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

show abstract

“…Susceptibility to this destructive process is a result of a complex interaction between genetic and environmental factors. 1,2 Numerous adoptive transfer studies in animal models (NOD mice and BB rat) indicate that both CD4 þ and CD8 þ T cells are involved in the pathogenesis of T1D. [3][4][5][6][7][8] In the pancreatic infiltrate (insulitis), both autoaggressive T cells (CD4 þ and CD8 þ ) and regulatory T cells (CD4 þ CD25 þ high T-cell or Tregs) with suppressive function are present.…”

Section: Introductionmentioning

confidence: 99%

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

et al. 2009

View full text Add to dashboard Cite

Type 1 diabetes (T1D) has a strong genetic component and the major locus lies in the HLA DQB1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4 þ CD25 þ high T-cell subset (Treg) in human subjects with recent-onset T1D and in multiple autoantibody-positive, high at-risk individuals. Tregs normally inhibit or delay onset of T1D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DQB1 genotypes are associated with increased CD4 þ CD25 þ high T-cell apoptosis. HLA DQ-based genetic risk status was significantly associated with CD4 þ CD25 þ high T-cell apoptosis, after adjustment for age, gender and phenotypic status (n ¼ 83, F ¼ 4.04 (d.f. ¼ 3), P ¼ 0.01). Unaffected, autoantibody-negative high risk HLA DQB1 control subjects showed increased CD4 þ CD25 þ high apoptosis levels compared with low risk HLA DQB1 control subjects (n ¼ 26, P ¼ 0.002), confirming that the association precedes disease. The association of specific HLA DQB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DQB1*0302, DQB1*0201 and HLA DQB1*0602 alleles. Our study shows an association of HLA DQB1 genotypes with CD4 þ CD25 þ high T-cell apoptosis, which implicates CD4 þ CD25 þ high T-cell apoptosis as a new intermediate trait for T1D.

show abstract

“…Consequently, subjects with T1DM are usually dependent on insulin injections for life (1)(2)(3). Markers of autoimmune beta-cell destruction include autoantibodies to insulin, to the islets of Langerhans, to glutamic acid decarbo xylase (GAD65), to beta-cell-specific zinc transporter ZnT8, and to tyrosine phosphatases IA-2 and IA-2b.…”

Section: Introductionmentioning

confidence: 99%

The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus

Bouças

Oliveira

Canani

et al. 2013

Arq Bras Endocrinol Metab

View full text Add to dashboard Cite

Type 1 diabetes mellitus (T1DM) is a chronic, progressive, autoimmune disease characterized by metabolic decompensation frequently leading to dehydration and ketoacidosis. Viral pathogens seem to play a major role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, enteroviruses have been consistently associated with T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The IFIH1 gene encodes a cytoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, playing a role in the innate immune response triggered by viral infection. Binding of dsRNA to this PRR triggers the release of proinflammatory cytokines, such as interferons (IFNs), which exhibit potent antiviral activity, protecting uninfected cells and inducing apoptosis of infected cells. The IFIH1 gene appears to play a major role in the development of some autoimmune diseases, and it is, therefore, a candidate gene for T1DM. Within this context, the objective of the present review was to address the role of IFIH1 in the development of T1DM. Arq Bras Endocrinol Metab. 2013;57(9):667-76 Keywords Autoimmunity; type 1 diabetes mellitus; viral infection; IFIH1 RESUMO O diabetes melito tipo 1 (T1DM) é uma doença autoimune crônica e progressiva caracterizada por descompensações metabólicas frequentemente acompanhadas por desidratação e cetoacidose. Os agentes virais parecem ter um papel importante no desencadeamento da destruição autoimune que leva ao desenvolvimento do T1DM. Entre as cepas virais estudadas até agora, a família dos enterovírus foi consistentemente associada ao surgimento da doença em humanos. Um dos mediadores do dano viral é o RNA fita dupla (RNAfd) gerado durante a replicação e transcrição de RNA e DNA viral. O gene IFIH1 codifica um receptor citoplasmático pertencente à família dos pattern-recognition receptors (PRRs) que reconhece o RNAfd, tendo um papel importante na resposta imune inata desencadeada por infecção viral. A ligação do RNAfd a essa PRR desencadeia a liberação de citocinas pró-inflamatórias como interferons (IFNs), os quais exibem uma potente ação antiviral e têm como objetivo proteger as células não infectadas e induzir apoptose naquelas já contaminadas. O gene IFIH1 parece ter uma participação importante no desenvolvimento de algumas doenças autoimunes. Por isso, esse gene é um candidato ao desenvolvimento do T1DM. Dentro desse contexto, o objetivo da presente revisão foi abordar o papel do IFIH1 no desenvolvimento do T1DM. Arq Bras Endocrinol Metab.2013;57(9):667-76 Descritores Autoimunidade; diabetes melito tipo 1; infecção viral; IFIH1

show abstract

Mediators and mechanisms of pancreatic beta-cell death in type 1 diabetes

Cited by 132 publications

References 61 publications

Cytokine-induced human islet cell death in vitro correlates with a persistently high phosphorylation of STAT-1, but not with NF-κB activation

Cytokine-induced human islet cell death in vitro correlates with a persistently high phosphorylation of STAT-1, but not with NF-κB activation

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus

Contact Info

Product

Resources

About