Cytokine- or chemically derived nitric oxide alters the expression of proteins detected by two-dimensional gel electrophoresis in neonatal rat islets of Langerhans.

John, Nerys; Andersen, Henrik U; Fey, Stephen J.; Larsen, Peter Mose; Roepstorff, Peter; Larsen, Martin R.; Pociot, Flemming; Karlsen, Allan E.; Nerup, Jørn; Green, Irene C.; Mandrup‐Poulsen, Thomas

doi:10.2337/diabetes.49.11.1819

Cited by 46 publications

(43 citation statements)

References 94 publications

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“…NO modifies the expression of several genes and proteins in beta cells [10,44,45]. The addition of the iNOS inhibitor L-MA prevented cytokine-induced NO production by the human islets, but did not affect the induction of mRNAs encoding IL-15 and the chemokines analyzed (Fig.…”

Section: Cytokines Induce Il-15 Ip-10 Mip-3α and Fractalkine Mrna Imentioning

confidence: 90%

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

et al. 2003

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Aims/hypothesis. Cytokines and chemokines are important mediators of immune responses due to their ability to recruit and activate leukocytes. Using microarray analysis we observed that rat beta cells exposed to IL-1β and IFN-γ have increased mRNA levels of chemokines and IL-15. The aim of this study was to characterize the expression of IP-10, MIP-3α, fractalkine and IL-15 in rat beta cells, human pancreatic islets, and in islets isolated from NOD mice, both during the pre-diabetic period and following islet transplantation. Methods. FACS-purified rat beta cells and human islets were cultured with IL-1β, IFN-γ and/or TNF-α. Islets were isolated from NOD or BALB/c mice at different ages. For syngeneic islet transplantation, 2-or 3-week-old NOD islets were grafted under the kidney capsule of spontaneously diabetic NOD recipients. Chemokine and IL-15 mRNA expression and protein release were evaluated, respectively, by RT-PCR and ELISA.Results. Human islets and rat beta cells express IP-10, MIP-3α, fractalkine and IL-15 mRNAs upon exposure to cytokines. The expression of IL-15, IP-10 and fractalkine is regulated by IFN-γ, while the expression of MIP-3α is IL-1β-dependent. Moreover, cytokines induced IL-15, IP-10, Mig, I-TAC and MIP-3α protein accumulation in culture medium from human islets. In vivo, there was an age-related increase in IL-15, IP-10 and MIP-3α expression in islets isolated from NOD mice. Following syngeneic islet transplantation, increased expression of IL-1β, IFN-γ, fractalkine, IP-10, MCP-1 and MIP-3α mRNAs were observed in the grafts. Conclusion/interpretation. Cytokine-exposed islets or beta cells express chemokines and IL-15. This could contribute to the recruitment and activation of mononuclear cells and development of insulitis in early Type 1 diabetes and during graft destruction. [Diabetologia (2003) 46:255-266] Keywords Type 1 diabetes mellitus, chemokines, IL-15, NOD mice, beta cells, interferon-γ, interleukin-1β, pancreatic islets, islet transplantation, insulitis.

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Section: Cytokines Induce Il-15 Ip-10 Mip-3α and Fractalkine Mrna Imentioning

confidence: 90%

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

et al. 2003

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“…protein expression (John et al 2000, Mose Larsen et al 2001) of 'harmful' and 'protective' proteins in -cells. Our work has shown that a previously unreported potentially harmful action of cytokines is inhibition of an existing antioxidant defence.…”

Section: Discussionmentioning

confidence: 99%

Cytokines and nitric oxide inhibit the enzyme activity of catalase but not its protein or mRNA expression in insulin-producing cells

Sigfrid¹,

Cunningham²,

Beeharry³

et al. 2003

Journal of Molecular Endocrinology

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Pancreatic -cells have low activities of the antioxidant enzyme catalase. Nitric oxide interacts with the haem group of catalase inhibiting its activity. We have studied the activity of catalase in -cells under conditions mimicking prediabetes and in which nitric oxide is generated from cytokine treatment in vitro. We also studied whether there is regulation of catalase enzyme activity by nitric oxide at the protein or gene expression level. RINm5F insulin-producing cells, treated for 24 h with cytokines, showed increased medium nitrite production (17±2·2 vs 0·3±0·2 pmol/µg protein) and significantly decreased cellular catalase activity (42·4±4·5%) compared with control cells. A similar reduction was seen in catalase-overexpressing RIN-CAT cells and in rat or human pancreatic islets of Langerhans. Catalase activity was also suppressed by the long-acting nitric oxide donor diethylenetriamine/nitric oxide adduct (Deta-NO) and this inhibition was reversible. The inhibition of catalase activity by cytokines in RINm5F cells was significantly reversed by the addition of the nitric oxide synthase 2 (NOS2) inhibitors nitro monomethylarginine or N-(3-(aminomethyl)benzyl)acetamidine (1400W). Protein expression was found to be unchanged in cytokine-or Deta-NO-treated RINm5F cells, while mRNA expression was marginally increased. We have shown that inhibition of catalase activity by cytokines is nitric oxide dependent and propose that this inhibition may confer increased susceptibility to cytokine-or nitric oxide-induced cell killing.

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“…We have shown previously that IL-1β induces PIPP in islets [8,9,10]. PIPPs comprises up-regulation and down-regulation of protein expression and/or gelposition-shifts resulting from post-translatory modifications.…”

Section: Discussionmentioning

confidence: 96%

“…haeme oxygenases and manganese superoxide dismutase (MnSOD)] [5,6]. Many IL-1β effects are mediated by inducing the inducible nitric oxide syntase (iNOS) and its product, nitric oxide [7]; however, NO-independent mechanisms also occur [8,9,10]. We hypothesize that the beta cell, when exposed to IL-1β initiates a protective response in competition with a series of deleterious events, and that in beta cells the deleterious events prevail [3].…”

Section: Il-1β Induced Protein Changes In Diabetes Prone Bb Rat Isletmentioning

confidence: 99%

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IL-1β induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis

Sparre

Bjerre-Christensen

Larsen³

et al. 2002

Diabetologia

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Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is characterized by selective destruction of the insulin producing beta cells. Interleukin-1β (IL-1β) modulates the beta-cell function, protein synthesis, energy production and causes apoptosis. We have previously shown changes in the expression of 82 out of 1 815 protein spots detected by two dimensional gel electrophoresis in IL-1β exposed diabetes prone Bio Breeding (BB-DP) rat islets of Langerhans in vitro. The aim of this study was to identify the proteins in these 82 spots by mass spectrometry and compare these changes with those seen in IL-1β exposed Wistar Furth (WF) rat islets. Methods. The 82 protein spots, that changed expression after IL-1β exposure, were all re-identified on preparative gels of 200 000 neonatal WF rat islets, cut out and subjected to mass spectrometry for identification.Results. Forty-five different proteins were identified from 51 spots and grouped according to function: (i) energy transduction and redox potentials; (ii) glycolytic and Krebs cycle enzymes; (iii) protein, DNA and RNA synthesis, chaperoning and protein folding; (iv) signal transduction, regulation, differentiation and apoptosis; (v) cellular defence; and (vi) other functions. Comparison of IL-1β exposed BB-DP and WF islets showed common changes in 14 proteins and several proteins influencing similar pathways, suggesting that similar routes in the two strains lead to beta-cell destruction. Conclusion/interpretation. We demonstrate that proteome analysis is a powerful tool to identify proteins and pathways in BB-DP rat islets exposed to IL-1β. [Diabetologia (2002) 45:1550-1561

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Cytokine- or chemically derived nitric oxide alters the expression of proteins detected by two-dimensional gel electrophoresis in neonatal rat islets of Langerhans.

Cited by 46 publications

References 94 publications

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

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

Cytokines and nitric oxide inhibit the enzyme activity of catalase but not its protein or mRNA expression in insulin-producing cells

IL-1β induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis

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