Exenatide blocks JAK1-STAT1 in pancreatic beta cells

Couto, Francesca M.; Minn, Alexandra H.; Pise-Masison, Cynthia A.; Radonovich, Michael F.; Brady, John; Hanson, Matthew S.; Fernández, Luis A.; Wang, Ping; Kendziorski, Christina; Shalev, Anath

doi:10.1016/j.metabol.2007.02.004

Cited by 19 publications

(16 citation statements)

References 17 publications

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“…6). Exendin-4 is reported to decrease basal mRNA levels of JAK1 and STAT1 in human islets and in INS-1 cells, a rat insulinoma cell line [35]. We observed here a decrease in IFN-γ-stimulated STAT-1 protein levels pre-incubated with exendin-4 and phosphodiesterase inhibitors (Figs 3c, 7d).…”

Section: Discussionsupporting

confidence: 63%

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

et al. 2010

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Aims/hypothesis Exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, is reported to have modest antiinflammatory effects in addition to that of improving beta cell survival. We therefore sought to determine whether exendin-4 decreases expression of the gene encoding chemokine (C-X-C motif) ligand (CXCL)10, which plays a role in initiating insulitis in type 1 diabetes. Methods The expression of CXCL10 in human islets was determined at the mRNA level by real-time RT-PCR analysis and at the protein level by western blotting. The level of CXCL10 in culture medium was measured by ELISA. Pathway-specific gene expression profiling was carried out to determine the expression of a panel of genes encoding chemokines and cytokines in human islets exposed to cytokines. Results IFN-γ induced expression of CXCL10 through activation of signal transducer and activator of transcription-1 (STAT-1). A combination of cytokines (IL-1β, TNF-α and IFN-γ) showed strong synergy in the induction of numerous chemokines and cytokines through nuclear factor kappa B and STAT-1. Exendin-4 suppressed basal expression of several inflammatory mediators. In combination with phosphodiesterase inhibitors, exendin-4 also decreased IFN-γ-induced CXCL10 expression in human islets and in MIN6 cells (a mouse beta cell line), and its secretion into the culture medium. Exendin-4 action was mimicked by forskolin, an activator of adenylyl cyclase, and by dibutyryl cyclic AMP. Protein kinase A was not involved in mediating exendin-4 action on CXCL10. The mechanism of exendin-4's anti-inflammatory action involved decreases in STAT-1 levels. Conclusions/interpretation These findings suggest that the GLP-1-cyclic AMP pathway decreases islet inflammation in addition to its known effects on beta cell survival.

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Section: Discussionsupporting

confidence: 63%

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

et al. 2010

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“…22,23 WT B6 mice were treated with Exenatide and were used as BM donors for transplantation into C3H.SW recipients, which also received Exenatide after transplant but before DLI, to mimic STAT1 deficiency during engraftment. Indeed, similar to transplantation of STAT1-deficient BM, we found that Exenatide decreased GVHD scores ( Figure 1F) and attenuated weight loss ( Figure 1G).…”

Section: Discussionmentioning

confidence: 99%

Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD

Capitini

Nasholm

Chien

et al. 2014

Blood

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Key Points • STAT12/2 BM prevents GVHD induced by delayed donor lymphocyte infusion via the expansion of CD92 Siglec H hi pDCs, which are low producers of IFNa and IL-12.• pDCs recovered from STAT1 2/2 BM chimeras show increased expression of S100A8, S100A9, and STAT3.Selective targeting of non-T cells, including antigen-presenting cells (APCs), is a potential strategy to prevent graft-versus-host-disease (GVHD) but to maintain graft-versus-tumor (GVT) effects. Because type I and II interferons signal through signal transducer and activator of transcription-1 (STAT1), and contribute to activation of APCs after allogeneic bone marrow transplant (alloBMT), we examined whether the absence of STAT1 in donor APCs could prevent GVHD while preserving immune competence. 2/2 pDCs that were isolated after alloBMT showed increased gene expression of S100A8 and S100A9, and transplantation of S100A9 2/2 BM reduced GVHD-free survival. Finally, elevated STAT3 was found in STAT1 2/2 pDCs isolated after alloBMT. We conclude that interfering with interferon signaling in APCs such as pDCs provides a novel approach to regulate the GVHD/GVT axis. (Blood. 2014;124(12):1976-1986

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“…Interestingly, IFN-γ has also been shown to play a major role in β-cell dysfunction associated with chronic pancreatitis [11]. The different biological effects of IFN-γ have been connected with its action in regulating gene transcription [5,7,12].…”

mentioning

confidence: 99%

“…Janus family kinase 1 (JAK1)-signal transducer and activator of transcription 1(STAT1) signaling pathway are considered crucial transcription factors mediating the IFN-γ effects on β-cell apoptosis and the subsequent development of T1D [3,5,[12][13][14]. The JAK/STAT signaling cascade is an essential inflammatory signaling pathway that controls the immune responses [14].…”

mentioning

confidence: 99%

“…The JAK/STAT signaling cascade is an essential inflammatory signaling pathway that controls the immune responses [14]. It is a critical intracellular machinery of cytokines involved in gene expression and cellular activation, proliferation and differentiation [12,13]. IFN-γ has been found to activate the expression of target genes through binding of activated STAT1 proteins on a consensus element termed the IFN-γ-activated site (GAS) [15,16].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Insulin Micro-secretionin Patients with Long Duration Type 1 Diabetes: Implications of Interferon-γ?

Mormile¹

2014

J Diabetes Metab

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Exenatide blocks JAK1-STAT1 in pancreatic beta cells

Cited by 19 publications

References 17 publications

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD

Insulin Micro-secretionin Patients with Long Duration Type 1 Diabetes: Implications of Interferon-γ?

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