Acute cytokine-mediated downregulation of the zinc transporter ZnT8 alters pancreatic β-cell function

Muayed, Malek El; Billings, Liana K.; Raja, Meera; Zhang, Xiaomin; Park, Paul J.; Newman, Marsha V.; Kaufman, Dixon B.; O’Halloran, Thomas V.; Lowe, William L.

doi:10.1677/joe-09-0420

Cited by 46 publications

(46 citation statements)

References 73 publications

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“…The results of the present study, in agreement with the findings of previous studies (27,46), indicated that insulin secretion can be inhibited by proinflammatory cytokines causing dysregulation of β cells via ZnT8 downregulation, and a decrease in β cell number by affecting apoptosis. The current study showed that proinflammatory cytokines, TNF-α and IL-1β, downregulate ZnT8 protein expression in NIT-1 cells.…”

Section: A B Discussionsupporting

confidence: 93%

“…The current study showed that proinflammatory cytokines, TNF-α and IL-1β, downregulate ZnT8 protein expression in NIT-1 cells. This effect was previously observed in MIN6 cells (27), indicating that decreased ZnT8 expression may contribute to impaired β cell function and insulin secretion. ZnT8 is predominantly expressed in pancreatic islets, and is responsible for transporting zinc from the cytoplasm into insulin secretory vesicles, where insulin is stored as a solid hexamer bound with two Zn 2+ ions (15).…”

Section: A B Discussionsupporting

confidence: 77%

“…Furthermore, an autoantibody to ZnT8 is widely considered as a biomarker of autoimmune diabetes (23,24). There is also evidence that zinc has an anti-inflammatory effect, and that ZnT8 expression can be downregulated by proinflammatory cytokines, which are expressed at high levels in type 2 diabetes (25)(26)(27). Tumor necrosis factor α-induced protein-3 (TNFAIP3) is a zinc finger and ubiquitin-editing protein that is able to inhibit or promote the NF-κB signaling cascade by attaching to the K48-linked or K63-linked polyubiquitin chains, respectively (28,29).…”

Section: Introductionmentioning

confidence: 99%

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Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

Cheng¹,

Zhang²,

Chen³

2016

Experimental and Therapeutic Medicine

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Abstract. Zinc transporter 8 (ZnT8) is exclusively expressed in the pancreatic islet and is essential for insulin crystallization, hexamerization and secretion. Tumor necrosis factor α-induced protein-3 (TNFAIP3) is a zinc finger protein that serves a major role in the negative feedback regulation of NF-κB signaling in response to multiple stimuli, and is a central regulator of immunopathology. Although the role of TNFAIP3 in diabetes has been extensively studied, its effect on ZnT8 has not been fully elucidated. The present study aimed to verify whether proinflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), are able to affect ZnT8 expression in islet cells. In addition, the study aimed to determine the effect of TNFAIP3 overexpression on cytokine-altered ZnT8 activity, considering its effect on NF-κB signaling. Cell-based studies using NIT-1 cells overexpressing TNFAIP3 were used to assess the effect of cytokines on ZnT8 and NF-κB activation, as well as the effect of TNFAIP3 on ZnT8 expression. Western blot analysis and immunofluorescence staining were employed to determine the protein expression and NF-κB activation, respectively. The results indicated that cytokine stimulation led to TNFAIP3 upregulation, ZnT8 downregulation and NF-κB activation. Furthermore, TNFAIP3 overexpression protected ZnT8 from cytokine-induced downregulation. In conclusion, the current results suggest that inflammation or TNFAIP3 dysfunction may be involved in the pathogenesis of diabetes via ZnT8 expression, besides from islet cell apoptosis. In addition, restricting inflammation and enhancing TNFAIP3 expression may exert a positive effect in diabetes prevention, treatment and pancreatic cell transplantation. IntroductionDiabetes, a class of metabolic diseases that are prevalent worldwide affecting 422 million people in 2014 according to the World Health Organization (1), is characterized by hyperglycemia and can cause severe damage to different organs, particularly the eyes, kidneys, nerves, heart and blood vessels. According to the American Diabetes Association, the disease can be classified into two main types, including type 1 and type 2 diabetes (2). Type 1 diabetes results from a cell-mediated autoimmune attack on β cells, whereas type 2 diabetes is a low-grade, chronic inflammatory disease that shares a common final pathway with type 1 diabetes, in which activation of the nuclear factor κB (NF-κB) signaling pathway causes a reduction in pancreatic β cells (3-10).Zinc participates in numerous biological processes, and is essential for the correct processing, storage, secretion, and function of insulin in pancreatic β cells (11-13). Zinc flux is controlled by two types of transporters: The zinc transporter (ZnT; also known as SLC30A) family, and the Zrt-and Irt-like protein (ZIP) family. Typically, the ZnT family regulates Zn 2+ efflux out of the cytoplasm, while the ZIP family regulates Zn 2+ influx into the cytoplasm. Although 10 ZnTs and 14 ZIPs have been identified in mammals, ZnT8 is exclusiv...

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Section: A B Discussionsupporting

confidence: 93%

Section: A B Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

Cheng¹,

Zhang²,

Chen³

2016

Experimental and Therapeutic Medicine

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“…While 5 ng/ml IL-1β suppresses both the proliferation of β-cells and their secretion of insulin [21], lower IL-1β concentrations (e.g. 0.02 ng/ml) promote β-cell proliferation and insulin secretion [22].…”

Section: Il-1β Production Is Induced In T2d Isletsmentioning

confidence: 99%

Macrophages and islet inflammation in type 2 diabetes

Eguchi

Manabe

2013

Diabetes Obesity Metabolism

109

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Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion from pancreatic β-cells. Inflammatory cytokines, including tumour necrosis factor-α (TNF-α), have been shown to promote insulin resistance, and altered expression of cytokines (adipokines) in obese adipose tissue is thought to be an important link between obesity and insulin resistance. It is also becoming clear that inflammation plays a key role in the development of β-cell dysfunction. Inflammatory changes, including accumulation of macrophages, have been documented in T2D islets. Moreover, therapeutic inhibition of interleukin-1β (IL-1β) ameliorates β-cell dysfunction in humans. This review summarizes current understanding of the molecular mechanisms underlying inflammation within islets and its relation to β-cell dysfunction in T2D. A particular focus is on the physiological and pathological functions of macrophages within islets. Keywords: diabetes, fatty acid, inflammation, innate immunity, macrophage Date submitted 22 March 2013; date of final acceptance 27 April 2013 IntroductionIt is becoming increasingly clear that chronic inflammation is a crucial factor contributing to the development and progression of various chronic non-communicable diseases (NCDs), including cancer, type 2 diabetes (T2D), Alzheimer's disease and cardiovascular and renal diseases [1,2]. For instance, elevated levels of interleukin-1β (IL-1β), IL-6 and C-reactive protein (CRP) are predictive of T2D [3]. Similarly, elevated circulating levels of proinflammatory cytokines, such as tumour necrosis factor-α (TNF-α), IL-6, IL-1β and IL-18, have all been observed in patients with chronic heart failure, where they correlate positively with disease severity [4]. These findings highlight to the pivotal involvement of inflammation in the progression of NCDs.Acute inflammation is primarily a protective response to infection or injury. Acute inflammatory processes deliver leukocytes and plasma proteins, such as antibodies, to sites of infection or tissue injury [5], where they act to restore tissue homeostasis. Morphologically, acute inflammation is manifested by vascular changes, oedema and predominantly neutrophilic infiltration, which cause the four cardinal signs of inflammation: rubor (redness), tumour (swelling), calor (heat) and dolor (pain). Although chronic inflammation may follow acute inflammation, in the most common NCDs of today, it probably begins insidiously as a low-grade, smouldering response with no manifestation of an acute reaction characterized by the cardinal signs [6].Insulin resistance and β-cell dysfunction are the two major mechanisms underlying T2D. Moreover, proinflammatory signalling pathways can inhibit insulin signalling [7,8] ,Correspondence to: Ichiro Manabe, Department of Cardiovascular Medicine, Graduate School of MedicineThe University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. E-mail: manabe-tky@umin.ac.jp providing a link between inflammation and insulin resistance. For instance, inhibition of the inflamm...

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“…Twenty micrograms of protein were separated by 10% SDS-PAGE and transferred to a polyvinylidene fluoride membrane in a semidry apparatus. Western blot analyses were performed as previously described (El Muayed et al 2010). For SP-D samples, both reduced and nonreduced protein samples were examined.…”

Section: Western Blotmentioning

confidence: 99%

Regulation of pancreatic islet gene expression in mouse islets by pregnancy

Layden

Durai²,

Newman³

et al. 2010

Journal of Endocrinology

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Pancreatic b cells adapt to pregnancy-induced insulin resistance by unclear mechanisms. This study sought to identify genes involved in b cell adaptation during pregnancy. To examine changes in global RNA expression during pregnancy, murine islets were isolated at a time point of increased b cell proliferation (E13 . 5), and RNA levels were determined by two different assays (global gene expression array and G-protein-coupled receptor (GPCR) array). Follow-up studies confirmed the findings for select genes. Differential expression of 110 genes was identified and follow-up studies confirmed the changes in select genes at both the RNA and protein level. Surfactant protein D (SP-D) mRNA and protein levels exhibited large increases, which were confirmed in murine islets. Cytokine-induced expression of SP-D in islets was also demonstrated, suggesting a possible role as an anti-inflammatory molecule. Complementing these studies, an expression array was performed to define pregnancy-induced changes in expression of GPCRs that are known to impact islet cell function and proliferation. This assay, the results of which were confirmed using realtime reverse transcription-PCR assays, demonstrated that free fatty acid receptor 2 and cholecystokinin receptor A mRNA levels were increased at E13 . 5. This study has identified multiple novel targets that may be important for the adaptation of islets to pregnancy.

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Acute cytokine-mediated downregulation of the zinc transporter ZnT8 alters pancreatic β-cell function

Cited by 46 publications

References 73 publications

Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

Tumor necrosis factor α-induced protein-3 protects zinc transporter 8 against proinflammatory cytokine-induced downregulation

Macrophages and islet inflammation in type 2 diabetes

Regulation of pancreatic islet gene expression in mouse islets by pregnancy

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