Deficiency of Atf3, an adaptive-response gene, protects islets and ameliorates inflammation in a syngeneic mouse transplantation model

Zmuda, Erik; Viapiano, Mariano S.; Grey, Shane T.; Hadley, Gregg A.; Garcı́a-Ocaña, Adolfo; Hai, Tsonwin

doi:10.1007/s00125-010-1696-x

Cited by 54 publications

(55 citation statements)

References 43 publications

(46 reference statements)

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“…Our results are in line with the later study, ATF3 knockdown increases TNF-a þ IFN-g-induced apoptosis in rodent b-cells and dispersed human islets, indicating an antiapoptotic action of this protein. The discrepancy between our data and results obtained in mouse ATF3 knockout cells (Zmuda et al, 2010b) may be due to an adaptation response of the full systemic knockout model, which is not present when ATF3 is silenced in adult rodent or human b-cells. Here we observed that ATF3 silencing decreases expression of the pro-survival protein Bcl-XL, thus sensitizing b-cells to apoptosis induction by pro-inflammatory cytokines as previously shown (Carrington et al, 2009;Gurzov et al, 2010).…”

Section: Discussioncontrasting

confidence: 99%

“…These findings provide a novel mechanistic regulation of the ATF3 gene by JunB in the context of inflammation. It has been reported that ATF3 knockout islets are resistant to pro-inflammatory cytokines (Zmuda et al, 2010b). On the other hand, subsequent data from the same group suggested that b-cell function is inhibited in ATF3-deficient mouse islets (Zmuda et al, 2010a).…”

Section: Discussionmentioning

confidence: 99%

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Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation

et al. 2011

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Destruction of insulin-producing pancreatic b-cells by local autoimmune inflammation is a hallmark of type 1 diabetes. Histochemical analysis of pancreases from non-obese diabetic mice indicated activation of the transcription factor JunB/AP-1 (activator protein-1) after autoimmune infiltration of the islets. In vitro studies demonstrated that the cytokines tumor necrosis factor (TNF)-a and interferon (IFN)-c induce JunB expression as a protective mechanism against apoptosis in both human and rodent b-cells. The gene network affected was studied by microarray analysis showing that JunB regulates nearly 20% of the cytokine-modified b-cell genes, including the transcription factor ATF3. Direct transcriptional induction of ATF3 by JunB is a key event for b-cell survival after TNF-a þ IFN-c treatment. Moreover, pharmacological upregulation of JunB/ATF3 via increased cAMP protected rodent primary b-cells and human islet cells against pro-inflammatory mediators. These results were confirmed in genetically modified islets derived from Ubi-JunB transgenic mice. Our findings identify ATF3 as a novel downstream target of JunB in the survival mechanism of b-cells under inflammatory stress.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation

et al. 2011

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“…ATF3 can act as either an activating or repressing transcription factor for many other genes and is therefore considered an adaptive-response gene. Previous studies have shown that depending on its dimeric state (homodimer versus heterodimer), upregulation of ATF3 can be pro- or anti-inflammatory (53)(54)(55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways

Aung¹,

Altman²,

Nyunt³

et al. 2016

Journal of Lipid Research

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Vascular cognitive impairment (VCI), a form of dementia caused by cerebrovascular disease, accounts for nearly 20% of cognitive dysfunction in the United States, and yet our understanding of the cerebrovascular disease processes underlying this dysfunction remains limited (1). Our understanding of vascular pathology in atherosclerotic cardiovascular disease (ASCVD) and the systemic circulation is more advanced and suggests important avenues of investigation, given the overlap of risk factors and epidemiology between ASCVD and cerebrovascular disease (2).Epidemiological evidence suggests a diet high in saturated fat and cholesterol negatively affects the health of the vasculature and contributes to the detrimental inflammatory injury that occurs in ASCVD and cerebrovascular disease (3-8). Studies also suggest that high levels of saturated fats and cholesterol contribute to the risk of developing VCI (9-14). Chronic intermittent vascular injury, as occurs over the course of decades of consumption of highfat meals, may significantly contribute to the long-term

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“…The process of isolation is fairly stressful on the islets; histopaque is toxic, shaking and centrifugation steps induce sheer stress, and the removal from host blood supply as well as in vitro culture can induce hypoxia. We and others have shown that isolation induces beta-cell death [4][5] . The effect from these stresses is seen by the sloughing of cells from the periphery of the islet and the darkening and expulsion of the central core of the islet (central necrosis).…”

Section: Working With Isolated Isletsmentioning

confidence: 80%

“…Fill a spray bottle with 70% ethanol. 4. Set up a dissecting microscope with an adequate light source on a lab bench or in a hood.…”

Section: Surgical Proceduresmentioning

confidence: 99%

A Method for Murine Islet Isolation and Subcapsular Kidney Transplantation

Zmuda

Powell

Hai

2011

JoVE

108

105

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Since the early pioneering work of Ballinger and Reckard demonstrating that transplantation of islets of Langerhans into diabetic rodents could normalize their blood glucose levels, islet transplantation has been proposed to be a potential treatment for type 1 diabetes 1,2 . More recently, advances in human islet transplantation have further strengthened this view 1,3 . However, two major limitations prevent islet transplantation from being a widespread clinical reality: (a) the requirement for large numbers of islets per patient, which severely reduces the number of potential recipients, and (b) the need for heavy immunosuppression, which significantly affects the pediatric population of patients due to their vulnerability to long-term immunosuppression. Strategies that can overcome these limitations have the potential to enhance the therapeutic utility of islet transplantation.Islet transplantation under the mouse kidney capsule is a widely accepted model to investigate various strategies to improve islet transplantation. This experiment requires the isolation of high quality islets and implantation of islets to the diabetic recipients. Both procedures require surgical steps that can be better demonstrated by video than by text. Here, we document the detailed steps for these procedures by both video and written protocol. We also briefly discuss different transplantation models: syngeneic, allogeneic, syngeneic autoimmune, and allogeneic autoimmune.

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Deficiency of Atf3, an adaptive-response gene, protects islets and ameliorates inflammation in a syngeneic mouse transplantation model

Cited by 54 publications

References 43 publications

Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation

Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation

Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways

A Method for Murine Islet Isolation and Subcapsular Kidney Transplantation

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