Contribution of ductal cells to cytokine responses by human pancreatic islets.

Pavlović, Dejan; Chen, Meng-Chi; Bouwens, Luc; Eizirik, Décio L.; Pipeleers, Daniël

doi:10.2337/diabetes.48.1.29

Cited by 72 publications

(63 citation statements)

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“…Previous studies have shown that exposure of duct cells to pro-inflammatory cytokines such as IFN-γ, either alone or in combination with IL-1β, led to their stimulation [1,3,4]. In particular, we recently observed that IL-1-exposed duct cells synthesise and release TNF-α (B. Movahedi, unpublished results).…”

Section: Introductionmentioning

confidence: 73%

“…It has been proven that both cytokines have direct and indirect toxic effects on beta cells through the induction of reactive oxygen intermediates and nitric oxide [4,38,39,40,41,42,43]. Besides its toxic effect, TNF-α could also influence adaptative immune responses directed against beta cells.…”

Section: Discussionmentioning

confidence: 99%

“…Human non-endocrine pancreatic duct cells were isolated from pancreases obtained from adult heart-beating organ donors as previously described [4], following guidelines of protocols that were approved by the local ethics committee. The organs were procured by European hospitals affiliated with the Eurotransplant Foundation (Leiden, The Netherlands) and sent to the Human Beta Cell Bank in Brussels (Belgium) for the preparation of isolated fractions.…”

Section: Methodsmentioning

confidence: 99%

“…There is suggestive evidence that pancreatic ducts are potential sites for beta cell neogenesis [1,2,3,4,5,6,7]. Duct cells were also shown to produce nitric oxide [4] and to express MHC class II [3], leading to proposals that they might contribute to beta cell damage in Type 1 diabetes mellitus [8]. In the transplantation setting, islet suspensions prepared from human pancreases contain a high proportion of non-endocrine duct cells [9,10], implying that these cells could affect graft acceptance.…”

Section: Introductionmentioning

confidence: 99%

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CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

Vosters

Beuneu

Nagy³

et al. 2004

Diabetologia

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Aims/hypothesis. Human pancreatic duct cells are closely associated with islet beta cells, and contaminate islet suspensions transplanted in Type 1 diabetes mellitus patients. Activated duct cells produce cytotoxic mediators and possibly contribute to the pathogenesis of Type 1 diabetes mellitus or islet graft rejection. As CD40 transduces activation signals involved in inflammatory and immune disorders, we investigated CD40 expression on duct cells and their response to CD40 engagement. Methods. CD40 expression on human pancreatic duct cells was analysed by flow cytometry and immunohistochemical analyses. To assess the function of CD40 expression on duct cells, activation of the transcription factor nuclear factor-kappa B was determined using electrophoretic mobility shift assay and ELISA. Cytokine mRNA levels were quantified by real-time RT-PCR, and protein levels by Luminex technology. Results. Isolated human pancreatic duct cells and Capan-2 cell lines were found to express constitutively CD40. The expression of CD40 on duct cells was confirmed in vivo on human normal and pathological pancreatic specimens. CD40 ligation on Capan-2 cells induced rapid nuclear factor-kappa B activation, and supershift assays demonstrated that p50/p65 heterodimers and p50/p50 homodimers were present in the activated complexes in the nucleus. This activation was accompanied by tumour necrosis factor-α and interleukin-1β mRNA accumulation. Tumour necrosis factor-α protein secretion was confirmed in CD40-activated Capan-2 cells and in isolated human pancreatic duct cells. Conclusions/interpretation. Interaction between activated T lymphocytes expressing CD40 ligand and duct cells expressing CD40 may contribute to the immune responses involved in Type 1 diabetes mellitus and islet graft rejection. Interfering with CD40-mediated duct cell activation could alleviate beta cell damage of immune origin.

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Section: Introductionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

Vosters

Beuneu

Nagy³

et al. 2004

Diabetologia

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“…It is important to know whether a similar process can occur in human islet grafts which are known to be heavily contaminated by pancreatic duct cells [19,20,21]. To investigate this possibility we prepared human pancreatic duct cells [22,23] and followed their cellular composition and cell population volumes over 10 weeks after transplantation in nude mice.…”

mentioning

confidence: 99%

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

et al. 2003

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Aims/hypothesis. Pancreatic ducts are considered as potential sites for neogenesis of beta cells. In vitro studies have reported formation of islets from postnatal human and rodent duct tissue. We examined whether postnatal human duct-cell preparations can generate new beta cells after transplantation. Methods. Pancreatic duct cells were prepared from the non-endocrine fraction of human donor pancreases that were processed for islet-cell isolation. Grafts containing 0.5 million duct cells with 1% contaminating insulin-positive cells were implanted under the kidney capsule of normoglycaemic nude mice. At 0.5 and 10 weeks post-transplantation, implants were examined for their cellular composition and for the volumes of their composing cell populations, i.e. cytokeratin 19-positive duct cells, synaptophysin-, insulin-and glucagon-positive endocrine cells. Results. Between week 0.5 and 10, duct-cell volume decreased by at least 90% whereas the change in insulin-positive cell volume depended on donor age. Implants from donors over10 years had a threefold decrease in their insulin-positive cell volume, while those from donors under 10 years had a 2.5-fold increase. After 10 weeks, the implants from the younger donors consisted of 19% insulin-positive cells occurring as single units or small cell clusters. Three percent of these insulin-positive cells also expressed the ductal marker CK 19 and were consistently found in conjunction with ductal epithelia; up to 1% was positive for the proliferation marker BrdU and located in small endocrine cell clusters. Conclusions/interpretation. These data indicate that duct cell preparations from donors under 10 years can generate insulin-positive cells. This process might involve differentiation of CK 19-positive-insulin cells that are formed at the duct epithelia as well as proliferation of insulin-positive cells within endocrine cell aggregates. [Diabetologia (2003) 46:830-838]

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Multiple low-dose and single high-dose treatments with streptozotocin do not generate nitric oxide

et al. 2000

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Streptozotocin (STZ) is a widely used diabetogenic agent that damages pancreatic islet beta cells by activating immune mechanisms, when given in multiple low doses, and by alkylating DNA, when given at a single high dose. Actually, STZ contains a nitroso moiety. Incubation of rat islets with this compound has been found to generate nitrite; moreover, photoinduced NO production from STZ has been demonstrated. These reports have suggested that direct NO generation may be a mechanism for STZ toxicity in diabetogenesis. Several other studies have denied such a mechanism of action. This study has shown that (1) the multiple low-dose (MLDS) treatment does not stimulate NO production at the islet level; in fact, nitrite + nitrate levels and aconitase activity (also in the presence of an NO-synthase inhibitor, namely NAME) remain unmodified; RT-PCR analysis demonstrates that this treatment does not stimulate iNOS activity; (2) the high-dose (HDS) treatment does not stimulate NO production; in fact nitrite + nitrate levels remain unmodified and iNOS mRNA levels are not altered, although aconitase activity is significantly decreased. Moreover, we have confirmed that the MLDS treatment is able to decrease SOD activity by day 11 and that STZ, given in a single high dose, transiently increases superoxide dismutase (SOD) values (24 h from the administration), then dramatically lowers SOD levels. On the basis of our results, we conclude that STZ, "in vivo" is unable to generate NO, both as a MLDS or HDS treatment, thus excluding that NO exerts a role in streptozotocin-dependent diabetes mellitus.

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Contribution of ductal cells to cytokine responses by human pancreatic islets.

Cited by 72 publications

References 0 publications

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

CD40 expression on human pancreatic duct cells: role in nuclear factor-kappa B activation and production of pro-inflammatory cytokines

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

Multiple low-dose and single high-dose treatments with streptozotocin do not generate nitric oxide

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