scholarly journals IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

2001 ◽  
Vol 166 (7) ◽  
pp. 4481-4489 ◽  
Author(s):  
Kyoungho Suk ◽  
Sunshin Kim ◽  
Yun-Hee Kim ◽  
Kyoung-Ah Kim ◽  
Inik Chang ◽  
...  
Keyword(s):  
Cell Death ◽  
Autoimmune Diabetes ◽  
Pancreatic Β Cell ◽  
Regulatory Factor ◽  
Β Cell ◽  
Tnf Α ◽  
Ifn Γ

scholarly journals Differential regulation of pro-inflammatory cytokine signalling by protein tyrosine phosphatases in pancreatic β-cells

2017 ◽  
Vol 59 (4) ◽  
pp. 325-337 ◽  
Author(s):  
William J Stanley ◽  
Prerak M Trivedi ◽  
Andrew P Sutherland ◽  
Helen E Thomas ◽  
Esteban N Gurzov
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Protein Tyrosine Phosphatases ◽  
Negative Regulator ◽  
Tyrosine Phosphatases ◽  
Β Cells ◽  
Β Cell ◽  
Protein Tyrosine ◽  
Tnf Α ◽  
Ifn Γ

Type 1 diabetes (T1D) is characterized by the destruction of insulin-producing β-cells by immune cells in the pancreas. Pro-inflammatory including TNF-α, IFN-γ and IL-1β are released in the islet during the autoimmune assault and signal in β-cells through phosphorylation cascades, resulting in pro-apoptotic gene expression and eventually β-cell death. Protein tyrosine phosphatases (PTPs) are a family of enzymes that regulate phosphorylative signalling and are associated with the development of T1D. Here, we observed expression of PTPN6 and PTPN1 in human islets and islets from non-obese diabetic (NOD) mice. To clarify the role of these PTPs in β-cells/islets, we took advantage of CRISPR/Cas9 technology and pharmacological approaches to inactivate both proteins. We identify PTPN6 as a negative regulator of TNF-α-induced β-cell death, through JNK-dependent BCL-2 protein degradation. In contrast, PTPN1 acts as a positive regulator of IFN-γ-induced STAT1-dependent gene expression, which enhanced autoimmune destruction of β-cells. Importantly, PTPN1 inactivation by pharmacological modulation protects β-cells and primary mouse islets from cytokine-mediated cell death. Thus, our data point to a non-redundant effect of PTP regulation of cytokine signalling in β-cells in autoimmune diabetes.

scholarly journals Pancreatic β-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis

PLoS ONE ◽  
2011 ◽  
Vol 6 (7) ◽  
pp. e22485 ◽  
Author(s):  
J. Jason Collier ◽  
Susan J. Burke ◽  
Mary E. Eisenhauer ◽  
Danhong Lu ◽  
Renee C. Sapp ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Cytokines ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Pro Inflammatory Cytokines

Estrogen reduces endoplasmic reticulum stress to protect against glucotoxicity induced-pancreatic β-cell death

2014 ◽  
Vol 139 ◽  
pp. 25-32 ◽  
Author(s):  
Suwattanee Kooptiwut ◽  
Pitchnischa Mahawong ◽  
Wanthanee Hanchang ◽  
Namoiy Semprasert ◽  
Suchada Kaewin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Endoplasmic Reticulum Stress ◽  
Pancreatic Β Cell ◽  
Β Cell

scholarly journals Nitric oxide interacts with cholinoceptors to modulate insulin secretion by pancreatic β cells

2020 ◽  
Vol 472 (10) ◽  
pp. 1469-1480
Author(s):  
Bashair M. Mussa ◽  
Ankita Srivastava ◽  
Abdul Khader Mohammed ◽  
Anthony J. M. Verberne
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Cell Viability ◽  
Combined Treatment ◽  
No Production ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Tnf Α ◽  
Ifn Γ

Abstract Dysfunction of the pancreatic β cells leads to several chronic disorders including diabetes mellitus. Several mediators and mechanisms are known to be involved in the regulation of β cell secretory function. In this study, we propose that cytokine-induced nitric oxide (NO) production interacts with cholinergic mechanisms to modulate insulin secretion from pancreatic β cells. Using a rat insulinoma cell line INS-1, we demonstrated that β cell viability decreases significantly in the presence of SNAP (NO donor) in a concentration- and time-dependent manner. Cell viability was also found to be decreased in the presence of a combined treatment of SNAP with SMN (muscarinic receptor antagonist). We then investigated the impact of these findings on insulin secretion and found a significant reduction in glucose uptake by INS-1 cells in the presence of SNAP and SMN as compared with control. Nitric oxide synthase 3 gene expression was found to be significantly reduced in response to combined treatment with SNAP and SMN suggesting an interaction between the cholinergic and nitrergic systems. The analysis of gene and protein expression further pin-pointed the involvement of M3 muscarinic receptors in the cholinergic pathway. Upon treatment with cytokines, reduced cell viability was observed in the presence of TNF-α and IFN-γ. A significant reduction in insulin secretion was also noted after treatment with TNF-α and IFN-γ and IL1-β. The findings of the present study have shown for the first time that the inhibition of the excitatory effects of cholinergic pathways on glucose-induced insulin secretion may cause β cell injury and dysfunction of insulin secretion in response to cytokine-induced NO production.

scholarly journals Autophagy couteracts weight gain, lipotoxicity and pancreatic β-cell death upon hypercaloric pro-diabetic regimens

2017 ◽  
Vol 8 (8) ◽  
pp. e2970-e2970 ◽  
Author(s):  
Álvaro F Fernández ◽  
Clea Bárcena ◽  
Gemma G Martínez-García ◽  
Isaac Tamargo-Gómez ◽  
María F Suárez ◽  
...  
Keyword(s):  
Cell Death ◽  
Weight Gain ◽  
Pancreatic Β Cell ◽  
Β Cell

scholarly journals Omega-3 Polyunsaturated Fatty Acids May Attenuate Streptozotocin-Induced Pancreatic β-Cell Death via Autophagy Activation in Fat1 Transgenic Mice

2015 ◽  
Vol 30 (4) ◽  
pp. 569 ◽  
Author(s):  
Won-Min Hwang ◽  
Dong-Ho Bak ◽  
Dong Ho Kim ◽  
Ju Young Hong ◽  
Seung-Yun Han ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Death ◽  
Transgenic Mice ◽  
Polyunsaturated Fatty Acids ◽  
Pancreatic Β Cell ◽  
Omega 3 ◽  
Β Cell

scholarly journals Pulmonary Inflammation Induced by Pseudomonas aeruginosa Lipopolysaccharide, Phospholipase C, and Exotoxin A: Role of Interferon Regulatory Factor 1

2002 ◽  
Vol 70 (3) ◽  
pp. 1352-1358 ◽  
Author(s):  
Catharina W. Wieland ◽  
Britta Siegmund ◽  
Giorgio Senaldi ◽  
Michael L. Vasil ◽  
Charles A. Dinarello ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pulmonary Inflammation ◽  
Interferon Regulatory Factor ◽  
Cell Infiltration ◽  
Exotoxin A ◽  
Regulatory Factor ◽  
Interferon Regulatory Factor 1 ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Chronic pulmonary infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) patients. P. aeruginosa lipopolysaccharide (LPS), phosholipase C (PLC), and exotoxin A (ETA) were evaluated for their ability to induce pulmonary inflammation in mice following intranasal inoculation. Both LPS and PLC induced high levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), IL-6, gamma interferon (IFN-γ), MIP-1α and MIP-2 in the lungs but did not affect IL-18 levels. ETA did not induce TNF-α and was a weak inducer of IL-1β, IL-6, macrophage inflammatory protein 1α (MIP-1α), and MIP-2. Remarkably, ETA reduced constitutive lung IL-18 levels. LPS was the only factor inducing IFN-γ. LPS, PLC, and ETA all induced cell infiltration in the lungs. The role of interferon regulatory factor-1 (IRF-1) in pulmonary inflammation induced by LPS, PLC, and ETA was evaluated. When inoculated with LPS, IRF-1 gene knockout (IRF-1 KO) mice produced lower levels of TNF-α, IL-1β, and IFN-γ than did wild-type (WT) mice. Similarly, a milder effect of ETA on IL-1β and IL-18 was observed for IRF-1 KO than for WT mice. In contrast, the cytokine response to PLC did not differ between WT and IRF-1 KO mice. Accordingly, LPS and ETA, but not PLC, induced expression of IRF-1 mRNA. IRF-1 deficiency had no effect on MIP-1α and MIP-2 levels and on cell infiltration induced by LPS, PLC, or ETA. Flow cytometric evaluation of lung mononuclear cells revealed strongly reduced percentages of CD8+ and NK cells in IRF-1 KO mice compared to percentages observed for WT mice. These data indicate that different virulence factors from P. aeruginosa induce pulmonary inflammation in vivo and that IRF-1 is involved in some of the cytokine responses to LPS and ETA.

Cadmium exposure induces pancreatic β-cell death via a Ca2+-triggered JNK/CHOP-related apoptotic signaling pathway

Toxicology ◽  
2019 ◽  
Vol 425 ◽  
pp. 152252 ◽  
Author(s):  
Cheng-Chin Huang ◽  
Chun-Ying Kuo ◽  
Ching-Yao Yang ◽  
Jui-Ming Liu ◽  
Ren-Jun Hsu ◽  
...  
Keyword(s):  
Cell Death ◽  
Signaling Pathway ◽  
Cadmium Exposure ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Apoptotic Signaling

Role of NF-κB in β-cell death

2008 ◽  
Vol 36 (3) ◽  
pp. 334-339 ◽  
Author(s):  
Danielle Melloul
Keyword(s):  
Cell Death ◽  
Lymphocytic Infiltration ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

Apoptotic β-cell death appears to be central to the pathogenesis of Type 1 diabetes mellitus and in islet graft rejection. The β-cell destruction is partially mediated by cytokines, such as IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and IFN-γ (interferon γ). IL-1β and TNFα mediate activation of the transcription factor NF-κB (nuclear factor κB) pathway. Use of a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), specifically expressed in β-cells, significantly reduced IL-1β+IFN-γ-induced apoptosis. Moreover, in vivo, it protected against multiple low-dose streptozocin-induced diabetes, with reduced intra-islet lymphocytic infiltration. Thus β-cell-specific activation of NF-κB is a key event in the progressive loss of β-cells in diabetes. Inhibition of this process could be a potential effective strategy for β-cell protection.

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