Article

Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor kappa-B (NF-κB) signalling in human islets and in a mouse beta cell line

Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045, USA.
Diabetologia (Impact Factor: 6.88). 05/2009; 52(6):1092-101. DOI: 10.1007/s00125-009-1331-x
Source: PubMed

ABSTRACT The destruction of pancreatic beta cells leading to type 1 diabetes in humans is thought to occur mainly through apoptosis and necrosis induced by activated macrophages and T cells, and in which secreted cytokines play a significant role. The transcription factor nuclear factor kappa-B (NF-kappaB) plays an important role in mediating the apoptotic action of cytokines in beta cells. We therefore sought to determine the changes in expression of genes modulated by NF-kappaB in human islets exposed to a combination of IL1beta, TNF-alpha and IFN-gamma.
Microarray and gene set enrichment analysis were performed to investigate the global response of gene expression and pathways modulated in cultured human islets exposed to cytokines. Validation of a panel of NF-kappaB-regulated genes was performed by quantitative RT-PCR. The mechanism of induction of BIRC3 by cytokines was examined by transient transfection of BIRC3 promoter constructs linked to a luciferase gene in MIN6 cells, a mouse beta cell line.
Enrichment of several metabolic and signalling pathways was observed in cytokine-treated human islets. In addition to the upregulation of known pro-apoptotic genes, a number of anti-apoptotic genes including BIRC3, BCL2A1, TNFAIP3, CFLAR and TRAF1 were induced by cytokines through NF-kappaB. Significant synergy between the cytokines was observed in NF-kappaB-mediated induction of the promoter of BIRC3 in MIN6 cells.
These findings suggest that, via NF-kappaB activation, cytokines induce a concurrent anti-apoptotic pathway that may be critical for preserving islet integrity and viability during the progression of insulitis in type 1 diabetes.

Full-text

Available from: Subbiah Pugazhenthi, Mar 12, 2014
0 Followers
 · 
215 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Synovial inflammation (synovitis) frequently accompanies intracapsular pathologic conditions of the temporomandibular joint (TMJ) such as internal derangement (ID) and/or osteoarthritis (OA), and is suggested to be associated with symptom severity. To identify the putative factors associated with synovitis, we investigated interleukin (IL)-1β- and/or tumor necrosis factor (TNF)-α-responsive genes of fibroblast-like synoviocytes (FLS) from patients with ID and/or OA of TMJ using microarray analysis. In this review, we first summarize the FLS of TMJ and the signaling pathways of IL-1β and TNF-α. Next, we show the up-regulated genes in FLS after stimulation with IL-1β or TNF-α, and summarize the gene functions based on recent studies. Among the top 10 up-regulated factors, molecules such as IL-6 and cycrooxygense-2 have been well characterized and investigated in the inflammatory responses and tissue destruction associated with joint diseases such as RA and OA, but the roles of some molecules remain unclear. The FLS reaction can lead to the synthesis and release of a wide variety of inflammatory mediators. Some of these mediators are detected in joint tissues and synovial fluids under intracapsular pathologic conditions, and may represent potential targets for therapeutic interventions in ID and/or OA of TMJ.
    Japanese Dental Science Review 10/2014; 51(1). DOI:10.1016/j.jdsr.2014.09.001
  • Source
    Type 1 Diabetes Complications, 11/2011; , ISBN: 978-953-307-788-8
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nonspecific inflammation in the transplant microenvironment results in β-cell dysfunction and death influencing negatively graft outcome. MicroRNA (miRNA) expression and gene target regulation in transplanted islets are not yet well characterized. We evaluated the impact of inflammation on miRNA expression in transplanted rat islets. Islets exposed in vitro to proinflammatory cytokines and explanted syngeneic islet grafts were evaluated by miRNA arrays. A subset of 26 islet miRNAs was affected by inflammation both in vivo and in vitro. Induction of miRNAs was dependent on NF-κB, a pathway linked with cytokine-mediated islet cell death. RT-PCR confirmed expression of 8 miRNAs. The association between these miRNAs and mRNA target-predicting algorithms in genome-wide RNA studies of β-cell inflammation identified 238 potential miRNA gene targets. Several genes were ontologically associated with regulation of insulin signaling and secretion, diabetes, and islet physiology. One of the most activated miRNAs was miR-21. Overexpression of miR-21 in insulin-secreting MIN6 cells downregulated endogenous expression of the tumor suppressor Pdcd4 and of Pclo, a Ca(2+) sensor protein involved in insulin secretion. Bioinformatics identified both as potential targets. The integrated analysis of miRNA and mRNA expression profiles revealed potential targets that may identify molecular targets for therapeutic interventions.
    Journal of Transplantation 05/2012; 2012:723614. DOI:10.1155/2012/723614

Similar Publications