Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis.

Зайцев, С. В.; Appelskog, Ioulia B.; Kapelioukh, Iouri L.; Yang, Shao Nian; Köhler, Martin; Efendić, Suad; Berggren, Per Olof

doi:10.2337/diabetes.50.2007.s70

Cited by 40 publications

(46 citation statements)

References 33 publications

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“…This is in agreement with the up-regulation of this gene reported by microarray analysis of INS-1 cells after a 2-h exposure to IL-1β and IFN-γ [10]. Recent studies have shown that calcineurin affects Ca 2+ -dependent signalling mechanisms in beta cell apoptosis [45], and inhibitors of calcineurin are able to prolong survival of allograft islet transplants [45,46,47,48]. This effect may be at least partly mediated through an ameliorated activation of NF-κB via a Ca 2+ -dependent mechanism [49].…”

Section: Discussionsupporting

confidence: 90%

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

et al. 2004

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Aims/hypothesis. Cytokines are important humoral mediators of beta cell destruction in autoimmune diabetes. The aim of this study was to identify novel cytokine-induced genes in insulin-producing RINm5F cells, which may contribute to beta cell death or survival. Methods. A global gene expression profile in cytokine-exposed insulin-producing RINm5F cells was achieved by automated restriction fragment differential display PCR. The expression of selected candidate genes was confirmed by real-time RT-PCR analysis. Results. Exposure of RINm5F cells to IL-1β or to a cytokine mixture (IL-1β, TNF-α, IFN-γ) for 6 h resulted in the differential expression of a functional gene cluster. Apart from the well-known up-regulation of the cytokine-responsive genes iNOS, NF-κB, MnSOD and Hsp70, several genes that belong to the functional cluster of the endocytotic pathway were identified. These endocytotic genes comprised: clathrin, megalin, synaptotagmin and calcineurin, which were up-regulated by IL-1β or the cytokine mixture.In contrast, the expression of the calcineurin inhibitor CAIN and of the GDP/GTP exchange protein Rab3 was down-regulated by cytokines. Other up-regulated cytokine-responsive genes were: agrin, murine adherent macrophage protein mRNA (MAMA) and transport-associated protein (TAP1/MTP), whereas the plasma membrane calcium ATPase (PMCA) 2 and PMCA 3 genes were down-regulated by cytokines. Conclusions/interpretation. Our results indicate that genes of the endocytotic pathway are regulated by pro-inflammatory cytokines. This might affect the density of cytokine receptors at the beta cell surface and concomitantly the sensitivity of the cells to cytokine toxicity. A better understanding of the functional cross-talk between endocytotic and cytokine signalling pathways could further the development of novel strategies to protect pancreatic beta cells against toxic effects of pro-inflammatory cytokines.

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Section: Discussionsupporting

confidence: 90%

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

et al. 2004

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“…In analogy to the effects of NCAM/FGFR signalling in neurons, an increase in the intracellular Ca 2+ concentration could facilitate IL-1β signalling to the MAPKs in beta cells. Inhibition of Ca 2+ influx has previously been shown to protect against cytokine-induced beta cell apoptosis, indicating that Ca 2+ plays a role in cytokine signalling [35,[45][46][47]. Further establishing Ca 2+ as the link is our observation that Ca 2+ does not seem to be involved in IL-1β-induced NF-κB activation [47] in accordance with the lack of effect of C3d on IL-1β-induced NF-κB activation.…”

Section: Discussionsupporting

confidence: 78%

IL-1β-induced pro-apoptotic signalling is facilitated by NCAM/FGF receptor signalling and inhibited by the C3d ligand in the INS-1E rat beta cell line

et al. 2006

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Aims/hypothesis: IL-1β released from immune cells induces beta cell pro-apoptotic signalling via mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). In neurons, the neural cell adhesion molecule (NCAM) signals to several elements involved in IL-1β-induced pro-apoptotic signalling in beta cells. Pancreatic beta cells express NCAM, but its biological effects in these cells are unclear. The aim of this study was to investigate whether there is cross-talk between NCAM signalling and cytokine-induced pro-apoptotic signalling. Materials and methods: Western blotting was used to investigate levels of NCAM and inducible nitric oxide synthase, phosphorylation of Src and MAPKs, and cleavage of caspase-3. MAPK activity was investigated with an in vitro kinase assay. Apoptosis was detected by cleaved caspase-3 and a Cell Death Detection ELISA plus assay. NCAM-induced fibroblast growth factor receptor (FGFR) activation was investigated in NCAM −/− Trex293 cells where FGFR phosphorylation was measured by Western blotting after NCAM transfection. Results: Preexposure of INS-1E cells to the FGFR-inhibitor SU5402, but not to the Src-inhibitor PP2, dose-dependently inhibited IL-1β-mediated MAPK activity. A synthetic peptide, C3d, reported to bind NCAM, did not activate MAPK or Akt as reported in neurons but inhibited IL-1β-induced MAPK activity, thereby mimicking the effect of SU5402. Furthermore, C3d inhibited NCAM-induced FGFR phosphorylation and apoptosis induced by IL-1β plus IFN-γ, but did not affect IL-1β-induced NF-κB signalling. Conclusions/interpretation: We suggest that NCAM signalling through FGFR is required for efficient IL-1β pro-apoptotic signalling by facilitating IL-1β-induced MAPK activation downstream of the NF-κB-MAPK branching point. Further, these data identify a novel function of C3d as an inhibitor of NCAM-induced FGFR activity and of IL-1β-induced MAPK activation in beta cells.

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“…Clonidine significantly decreases TNF-α production in macrophages and noradrenergic nerve terminals in in vivo lipopolysaccharide-treated mice (24). In type 2 diabetes, imidazoline compounds protect against proinflammatory interleukin 1ß-induced beta-cell apoptosis (25).…”

Section: Imidazoline and Natriuretic Peptidesmentioning

confidence: 98%

“…Inhibition of renal sympathetic activity and/or direct activation of kidney imidazoline I 1 -receptors induce diuresis and natriuresis (17,18), thus contributing to acute and long-term blood pressure control. In addition, the benefits of imidazoline compounds go beyond blood pressure control 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 through their cardioprotective effects, antiproliferative and anti-arrhythmic, as well as their anti-inflammatory actions (19)(20)(21)(22)(23)(24)(25). Moxonidine and rilmenidine reduce left ventricular hypertrophy in patients and rats (20)(21)(22).…”

Section: Imidazoline and Natriuretic Peptidesmentioning

confidence: 99%

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides

Mukaddam‐Daher

Gutkowska

2004

Braz J Med Biol Res

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Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I 1 -receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I 1 -receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I 1 -receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I 1 -receptors are involved in cardiovascular regulation. The presence of I 1 -receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 µg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 µg kg -1 h -1 , sc for 4 weeks) dosedependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1ß concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine. Correspondence S. Mukaddam-Daher

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Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis.

Cited by 40 publications

References 33 publications

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

IL-1β-induced pro-apoptotic signalling is facilitated by NCAM/FGF receptor signalling and inhibited by the C3d ligand in the INS-1E rat beta cell line

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides

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