IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

Cardozo, Alessandra K; Proost, Paul; Gysemans, Conny; Chen, MC; Mathieu, Chantal; Eizirik, Décio L.

doi:10.1007/s00125-002-1017-0

Cited by 179 publications

(163 citation statements)

References 79 publications

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“…Chemokines play an important role in the initiation of insulitis in type 1 diabetes and in islet graft rejection [12,13,23,24]. In this study, we demonstrate that exendin-4-mediated suppression of CXCL10 expression is enhanced by phosphodiesterase inhibitors in human islets and in a mouse beta cell line.…”

Section: Discussionmentioning

confidence: 49%

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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: Discussionmentioning

confidence: 49%

“…CXCL10 plays an important role in trafficking effector T cells to islets during insulitis in type 1 diabetes [12]. In NOD mice, CXCL10 production in islets is increased prior to initiation of insulitis [13]. CXCL10 neutralisation has been shown to suppress the incidence of diabetes in NOD mice [14].…”

Section: Introductionmentioning

confidence: 99%

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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“…Interferon-γ is also an important inducer of chemokine release by stressed pancreatic islets or beta cells [20,36,37]. Chemokines and their receptors are thought to play an important role in lymphocyte traffic.…”

Section: Discussionmentioning

confidence: 99%

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

Halteren¹,

Kardol²,

Mulder³

et al. 2004

Diabetologia

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Aims/hypothesis: An important prerequisite for the initiation of pancreatic islet inflammation is the recruitment of pathogenic T cells. We investigated the in vivo migration patterns of human islet-reactive T cell clones after transfer into compromised hosts. Methods: NOD-scid mice were injected with a mixture of human autoreactive T cells and antigen-presenting cells. Survival and migration of T cells was analysed by fluorescenceactivated cell sorter and immunohistochemical analysis of various tissues.

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“…Finally, all genes considered as increased or decreased in all three individual experiments and showing a change greater than 50% compared with controls were also included in the analysis. This multistep approach was validated by empirical comparison against our previous candidate-gene analysis of human and rat islets exposed to cytokines [1,19,20] and provided the final numbers of 945 and 1293 single genes modified by viral infection and cytokines, respectively. The agreement between the statistical and the Affymetrix approaches was 84 and 91% for virus-and cytokine-induced changes respectively.…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

“…IFIT1: 2 and 4 interferon-induced protein with tetratricopeptide repeats 1, 2 and 4 . IFITM1: interferon-induced transmembrane protein 1 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) . IFNB1: interferon β1, fibroblast .…”

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confidence: 99%

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

et al. 2005

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Aims/hypothesis: It is thought that enterovirus infections initiate or facilitate the pathogenetic processes leading to type 1 diabetes. Exposure of cultured human islets to cytolytic enterovirus strains kills beta cells after a protracted period, suggesting a role for secondary virusinduced factors such as cytokines. Methods: To clarify the molecular mechanisms involved in virus-induced beta cell destruction, we analysed the global pattern of gene expression in human islets. After 48 h, RNA was extracted from three independent human islet preparations infected with coxsackievirus B5 or exposed to interleukin 1β (50 U/ml) plus interferon γ (1,000 U/ml), and gene expression profiles were analysed using Affymetrix HG-U133A gene chips, which enable simultaneous analysis of 22,000 probe sets. Results: As many as 13,077 genes were detected in control human islets, and 945 and 1293 single genes were found to be modified by exposure to viral infection and the indicated cytokines, respectively. Four hundred and eighty-four genes were similarly modified by the cytokines and viral infection. Conclusions/ interpretation: The large number of modified genes observed emphasises the complex responses of human islet cells to agents potentially involved in insulitis. Notably, both cytokines and viral infection significantly (p<0.02) increased the expression of several chemokines, the cytokine IL-15 and the intercellular adhesion molecule ICAM-1, which might contribute to the homing and activation of mononuclear cells in the islets during infection and/or an early autoimmune response. The present results provide novel insights into the molecular mechanisms involved in viral-and cytokine-induced human beta cell dysfunction and death.

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IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

Cited by 179 publications

References 79 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

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

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