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  • 1
    Electronic Resource
    Electronic Resource
    Monocyte Function in IDDM Patients and Healthy Individuals (1990)
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 32 (1990), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Interleukin 1β(IL-1β) and tumour necrosis factor alpha (TNF-α) may be pathogenetically important in insulin-dependent diabetes mellitus (IDDM), which is associated with genes of the HLA region. Since a regulatory role of HLA region genes on monokine production may exist, we looked for an association between the monokine and prostaglandin E2 (PGE2) responses of monocytes (Mo) from 20 healthy males (18–50 years) with HLA-DR types relevant for IDDM susceptibility and resistance (DR 1,2, DR 1,3, DR 1,4, DR 3,4). Monokine assays were established and evaluated and the secretions of IL-1β, TNF-α, and PGE2 measured in Mo cultures (2 h, 6 h, 20 h) prepared by endotoxin-free techniques and stimulated by low-dose E. coli lipopolysaccharides (LPS). There were no significant associations between Mo responses and HLA-DR phenotype. Likewise, Mo from DR2 (n=5) and DR4 (n= 5) homozygous healthy males demonstrated no significant differences in monokine and PGE2 responses of Mo.In the HLA class III region a diallelic TNF-β gene Ncol polymorphism consisting of alleles of 5.5 kb and 10.5 kb was recently described and associated with susceptibility to autoimmune diseases including IDDM. We report that IL-1β and TNF-α responses of Mo from TNF-β 10.5 kb homozygous healthy individuals were significantly higher than for TNF-β 5.5/10.5 kb heterozygotes.IL-1β and TNF-α responses of Mo from males (18–35 years) with newly diagnosed (n= 10) and long-standing IDDM (n= 10) and from age- and HLA-DR-matched healthy males (n= 10) were studied. LPS, gamma interferon (IFN), and TNF-α-stimulated Mo cultures were investigated. No significant differences were found between Mo responses of IDDM patients and controls. IFN (1000 U/ml) in the presence of LPS significantly potentiated LPS-stimulated Mo TNF-α secretion and reduced the levels of IL-β immunoreactivity in Mo lysates. IFN and TNF-α did not have any effects on LPS-stimulated Mo secretion of IL-1 β immunoreactivity.We conclude that Mo IL-1β and TNF-α production is normal in patients with recent-onset and long-standing IDDM. The interindividual differences in monokine responses may be accounted for by the diallelic human TNF-β gene polymorphism rather than by HLA class II genes. This observation may be important for understanding the association of certain H LA haplotypes with autoimmune phenomena and disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-3083.1990.tb02924.x
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  • 2
    Electronic Resource
    Electronic Resource
    Dietary Supplementation with co-3-Polyunsaturated Fatty Acids Decreases Mononuclear Cell Proliferation and Interleukin-1β Content but not Monokine Secretion in Healthy and Insulin-Dependent Diabetic Individuals (1991)
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 34 (1991), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The effects of dietary supplementation with ω-3-polyunsaturated fatty acids (ω-3-PUFA) on the proliferative response of PBMC and on the secretion of monokines and arachidonic acid metabolites from PBMC and monocytes (Mo) from healthy subjects and patients with recent-onset insulin-dependent diabetes mellitus (IDDM) were examined. Three groups of eight to nine healthy individuals were randomized to either 2.0 g/day or 4.0 g/day of ω-3-PUFA devoid of vitamins A and D, or an isocaloric amount of placebo. Furthermore, eight patients with recent-onset IDDM received 4.0 g/day of ω-3-PUFA. IL-lβ production and TNF-α secretion was determined before and after 7 weeks of treatment, and 10 weeks after withdrawal of treatment. Significant increases in platelet and PBMC membrane eicosapentaenoic acid was found in ω-3-PUFA-treated individuals. ω-3-PUFA treatment significantly reduced the content of IL-Ib in lysates of PBMC, but did not affect PBMC or Mo secretion of IL-1β, TNF-α or prostaglandin E2 (PGE2) or PBMC leukotriene B4 (LTB4) secretion in healthy subjects or in IDDM patients. A significant inhibition of the PHA-stimulated. but not the spontaneous or PPD-stimulated, proliferative response of PBMC was observed in healthy and diabetic subjects treated with (o-3-PUFA. No correlation was found between PHA-stimulated PBMC proliferation and PBMC secretion of TNF-α and IL-1β. There were no significant differences in the spontaneous or the PPD-or PHA-stimulated proliferative responses of PBMC between diabetic and healthy individuals at entry. We conclude that although dietary supplementation with 4.0 g/day of ω-3-PUFA inhibits the proliferation of PBMC and reduces IL-I immunoreactivity in PBMC and Mo, it does not alter monokine, PGE2 or LTB4, secretion in healthy or IDDM subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-3083.1991.tb01563.x
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  • 3
    Electronic Resource
    Electronic Resource
    Identification of a Type 1 Diabetes-Associated CD4 Promoter Haplotype with High Constitutive Activity (2004)
    Oxford, UK; Malden, USA : Blackwell Science Ltd
    Scandinavian journal of immunology 59 (2004), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4+ T cells. We previously found linkage between a CD4-1188(TTTTC)5−14 promoter polymorphism and T1DM. In the present study, we screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC)5−14 alleles, and we observed nine CD4 promoter haplotypes, of which four are frequent. We genotyped the SNPs in 253 Danish T1DM families (1129 individuals) and found evidence for linkage and association of a CD4 (A4-1188T-1050G-521C-181) haplotype to T1DM. In reporter studies, we show that (1) the T1DM-associated CD4 haplotype encodes high constitutive promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP on stimulated CD4 promoter activity and the identification of a novel CD4 haplotype with high constitutive promoter activity that is linked and associated with T1DM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-3083.2004.01444.x
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  • 4
    Electronic Resource
    Electronic Resource
    Cytokines Cause Functional and Structural Damage to Isolated Islets of Langerhans (1985)
    Oxford, UK : Blackwell Publishing Ltd
    Allergy 40 (1985), S. 0 
    Details
    ISSN: 1398-9995
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Cytokines are soluble, antigen non-specific, non-immunoglobulin mediators produced and secreted by blood mononuclear cells interacting in the cellular immune-response. To test the possibility that cytokines participate in the autoimmune destruction of the pancreatic beta-cells leading to insulin-dependent diabetes mellitus, isolated human or rat islets of Langerhans were incubated for 7 days with cytokine-rich, cell-free supernatants of blood mononuclear cells from healthy human donors stimulated with or without purified protein derivative of tuberculin or phytohaemagglutinin. Glucose stimulated insulin-release, and contents of insulin and glucagon in islets incubated with cytokine-rich supernatants were markedly reduced. This impairment of islet function was due to a cytotoxic effect of cytokine-rich supernatants as judged by disintegration of normal light-microscopic morphology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1398-9995.1985.tb02681.x
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  • 5
    Electronic Resource
    Electronic Resource
    Interleukin 1β induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases
    Amsterdam : Elsevier
    Cytokine 6 (1994), S. 512-520 
    Details
    ISSN: 1043-4666
    Keywords: Aminoguanidine ; NAME ; glucagon ; insulin resistance ; leukocytes
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1016/1043-4666(94)90079-5
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  • 6
    Electronic Resource
    Electronic Resource
    Mechanisms of Pancreatic Islet Cell Destruction Dose-Dependent Cytotoxic Effect of Soluble Blood Mononuclear Cell Mediators on Isolated Islets of Langerhans (1986)
    Oxford, UK : Blackwell Publishing Ltd
    Allergy 41 (1986), S. 0 
    Details
    ISSN: 1398-9995
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Supernatants of peripheral blood mononuclear cells from healthy human donors stimulated with recall antigen (purified protein derivative of tuberculin) or lectin (phytohaemagglutinin) markedly inhibited the insulin release from isolated human and rat islets of Langerhans, and decreased rat islet contents of insulin and glucagons in a dose-dependent manner. A maximal effect on islet function was obtained with supernatant concentrations down to 5%. Supernatants of mononuclear cells stimulated with tuberculin were more potent than supernatants produced by lectin stimulation. Culture medium reconstituted with tuberculin or phytohaemagglutinin did not impair islet function. Electron microscopy demonstrated that supernatants were cytotoxic to islet cell. The cytotoxic mononuclear cell mediator(s) was non-dialysable, sensitive to heating to 56°C, labile even when stored at -70°C, but stable when lyophilised.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1398-9995.1986.tb02025.x
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  • 7
    Electronic Resource
    Electronic Resource
    Functional and morphological effects of interleukin-1β on the perfused rat pancreas (1990)
    Springer
    Diabetologia 33 (1990), S. 15-23 
    Details
    ISSN: 1432-0428
    Keywords: Interleukin-1 ; perfused rat pancreas ; insulin ; glucagon ; Type 1 (insulin-dependent) diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We recently reported a potentiating effect of recombinant human interleukin-1β on glucose-stimulated insulin release from the isolated perfused pancreas. With the aim of determining whether the stimulatory effect of recombinant interleukin-1β on the B cell in the intact gland was modulated by varying the concentration, time of exposure to recombinant interleukin-1β or B-cell activity, and to elucidate a possible mechanism of action, we measured in the perfused rat pancreas the release of insulin, glucagon and/or prostaglandin E2 according to the following three different protocols: (1) perfusion with 20 ng/ml of recombinant interleukin-1β for 92 min at 5 and 20 mmol/1 D-glucose (2) perfusion with varying concentrations of recombinant interleukin-1β ranging from 0.1×10−3 ng/ml to 100 ng/ml at 5 and 20 mmol/l D-glucose (3) perfusion with 20 ng/ml of recombinant interleukin-1β at 5,11 or 20 mmol/l D-glucose. Furthermore, in a separate set of experiments we examined the influence of the cytokine on the morphology of the endocrine pancreas. Interleukin-1β stimulated insulin secretion at 11 and 20 mmol/l D-glucose and potentiated first as well as second phase insulin release in a dose-dependent fashion, with decreasing effect at higher concentrations. Glucagon secretion was also stimulated by recombinant interleukin-1β, irrespective of increasing glucose (5, 11, 20 mmol/l) and insulin concentrations. The potentiating effect of recombinant interleukin-1β on insulin secretion was evident even after discontinued perfusion with the cytokine, suggesting a priming effect on B-cell function. Furthermore, we did not observe any relation between the recombinant interleukin-1β mediated insulin and glucagon release and prostaglandin E2. Electron microscopy of the pancreata perfused with recombinant interleukin-1β revealed significant B cell and to a lesser extent A-cell lysis as well as induction of cell protrusions (“blebs”) in B cells only, accompanied by peripheral degranulation and rearrangement of rough endoplasmatic reticulum. We suggest that in addition to a paracrine effect of locally produced interleukin-1β systemic interleukin-1β may have an endocrine effect on A- and B-cell function and viability. Interleukin-1β should be considered to be a physiological modulator of insulin and glucagon secretion e.g. during the acute phase response, but also as a pathogenetic factor in Type 1 (insulin-dependent) diabetes mellitus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00586456
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  • 8
    Electronic Resource
    Electronic Resource
    Repetitive in vivo treatment with human recombinant interleukin-1β modifies Beta-cell function in normal rats (1992)
    Springer
    Diabetologia 35 (1992), S. 331-339 
    Details
    ISSN: 1432-0428
    Keywords: Interleukin-1β ; Beta cells ; morphology ; glucose tolerance ; Type 1 (insulin-dependent) diabetes mellitus ; pathogenesis ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It is unknown whether interleukin-1 exerts a bimodal effect on Beta-cell function in vivo, and whether interleukin-1 has a diabetogenic action in normal animals. We therefore studied: (a) acute effects 2 h after an intraperitoneal bolus injection of 4 μg of recombinant human interleukin-1β per kg body weight on blood glucose, plasma levels of insulin, glucagon and corticosterone in Wistar Kyoto rats, either untreated or pre-treated with 4 μg/kg of interleukin-1 daily for 3 or 5 days; (b) the cumulative effects of repetitive intraperitoneal injections of 4 μg/kg interleukin-1 on blood glucose, glucose tolerance, plasma levels of insulin, glucagon and corticosterone, pancreatic insulin content and pancreatic ultrastructure; and (c) blood glucose and plasma concentrations of insulin, glucagon and corticosterone 10 h after the last of five intraperitoneal injections of interleukin-1, at which time point the inhibitory effect of short-term interleukin-1 exposure on insulin secretion reaches its nadir in vitro. A single injection of 4 μg/kg of interleukin-1 caused a slight, but significant lowering of blood glucose 2 h after interleukin-1 injection with no significant changes in plasma insulin and in spite of increases in plasma glucagon and corticosterone. A lowering of blood glucose 2 h after interleukin-1 administration was reproduced with 40, but not 0.4 μg/kg of interleukin-1, and was also seen in interleukin-1 pre-treated rats. Two hours after the fifth injection of interleukin-1, intraperitoneal glucose tolerance was impaired with elevated plasma insulin and corticosterone levels and increased pancreatic insulin content, indicating a state of insulin resistance. Blood glucose levels significantly increased time-dependently 4–10 h after the third and fifth injection of interleukin-1, and diabetic values (blood glucose 〉11.0 mmol/l) were observed 6 and 10 h after the fifth injection of interleukin-1. Ten hours after the fifth injection of interleukin-1, diabetic blood glucose levels were observed together with a 50% reduction in plasma insulin concentration. Ultrastructural examination showed no signs of Betacell lysis. In conclusion, interleukin-1 has bimodal effects on glucose homeostasis in vivo, a slight lowering of the blood glucose followed by impaired glucose tolerance and later by diabetic blood glucose levels. Two hours after the last of five daily injections of interleukin-1 impaired glucose tolerance is primarily caused by a state of insulin resistance, whereas diabetic blood glucose levels are associated with inhibition of insulin secretion. Thus, interleukin-1 causes a diabetic state in normal animals, but it remains to be demonstrated that administration of interleukin-1 to normal animals leads to permanent diabetes due to Beta-cell destruction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401200
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  • 9
    Electronic Resource
    Electronic Resource
    TNFα and IFNγ potentiate IL-1β induced mitogen activated protein kinase activity in rat pancreatic islets of Langerhans (2000)
    Springer
    Diabetologia 43 (2000), S. 1389-1396 
    Details
    ISSN: 1432-0428
    Keywords: Keywords c-jun N-terminal kinase, cytokines, ERK, extracellular-signal-regulated kinase, insulin-dependent diabetes mellitus, JNK, MAPK, p38, SAPK, signalling.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Interleukin-1 beta (IL-1β) in synergy with tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) is cytotoxic to pancreatic beta cells. Mitogen-activated protein kinase (MAPK) activity that is induced by interleukin-1 beta has been suggested to signal nitric oxide-dependent as well as nitric oxide-independent beta-cell destructive pathways. The aim of this study was to investigate if TNFα and IFNγ signal through mitogen-activated protein kinases in isolated rat islets of Langerhans and if they potentiate mitogen-activated protein kinase activity induced by IL-1β.¶Methods. Islets of Langerhans were isolated from 5- to 7-day-old Wistar rats and precultured for 7 days before stimulation with IL-1β, TNFα and/or IFNγ for 20 min followed by lysis. Kinase activity was measured with a whole cell lysate kinase assay and after immunoprecipitation of the kinase using immunocomplex kinase assay.¶Results. Exposure to IL-1β or TNFα significantly increased mitogen-activated protein kinase activity, whereas IFNγ tended to decrease extracellular-signal-regulated kinase activity. Further, TNFα and IFNγ were found to synergistically increase mitogen-activated protein kinase activity induced by IL-1β.¶Conclusion/interpretation. We hypothesise that the synergistic effect of IL-1β, TNFα and IFNγ in the functional inhibition and induction of cell death in pancreatic beta cells is signalled through a synergistic activation of mitogen-activated protein kinase activity [Diabetologia (2000) 43: 1389–1396].
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051544
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  • 10
    Electronic Resource
    Electronic Resource
    Affinity-purified human Interleukin I is cytotoxic to isolated islets of Langerhans (1986)
    Springer
    Diabetologia 29 (1986), S. 63-67 
    Details
    ISSN: 1432-0428
    Keywords: Autoimmunity ; pancreatic B cells ; cytotoxicity ; Interleukin-1 ; lymphokines ; macrophages ; pancreatic islets pathogenesis ; Type 1 (insulin-dependent) diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Addition of highly purified human Interleukin-1 to the culture medium of isolated rat islets of Langerhans for 6 days led to 88% inhibition of glucose-induced insulin-release, reduction of islet contents of insulin and glucagon to 31% and 8% respectively, and disintegration of the islets. These effects were dose-dependent and reproducible when using three different Interleukin-1 preparations. Highly purified human Interleukin-2, Lymphotoxin, Leucocyte Migration Inhibitory Factor and Macrophage Migration Inhibitory Factor were ineffective. These findings suggest that Interleukin-1 may play an important role in the molecular mechanisms underlying autoimmune B-cell destruction leading to Type 1 (insulin-dependent) diabetes mellitus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02427283
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