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Diabetologia

Published in:

01-10-2008 | Article

CD40 activation in human pancreatic islets and ductal cells

Authors: D. Klein, F. Timoneri, H. Ichii, C. Ricordi, R. L. Pastori

Published in: Diabetologia | Issue 10/2008

Abstract

Aims/hypothesis

CD40 expression on non-haematopoietic cells is linked to inflammation. We previously reported that CD40 is expressed on isolated human and non-human primate islets and its activation results in secretion of IL-8, macrophage inflammatory protein 1-beta (MIP-1β) and monocyte chemoattractant protein-1 (MCP-1) through nuclear factor-κB and extracellularly regulated kinases 1/2 pathways. The objective of this study was to identify the pattern of gene expression, and to study viability and functionality affected by CD40–CD40 ligand (CD40L) interaction in human islets. Furthermore, we have studied the CD40-mediated cytokine/chemokine profile in pancreatic ductal cells, as they are always present in human islet transplant preparations and express CD40 constitutively.

Methods

CD40–CD40L gene expression modulation was studied by microarray on islet cells depleted of ductal cells. Selected genes were validated by quantitative RT-PCR. The cytokine profile in purified ductal cells was evaluated by Luminex technology, based on the use of fluorescent-coated beads, known as microspheres, and capable of multiplex detection of proteins from a single sample. Glucose-stimulated insulin secretion and islet viability were assessed by perifusion and 7-aminoactinomycin D membrane exclusion, respectively.

Results

Statistical analysis of microarrays identified 30 genes exhibiting at least a 2.5-fold increase across all replicate arrays. The majority of them were related to oxidative stress/inflammation. Prominently upregulated were chemokine C-X-C motif ligand 1 (CXCL1), CXCL2 and CXCL3 belonging to the CXC family of chemokines related to IL-8. CD40-mediated CXCL1 secretion was confirmed by ELISA. The viability or in vitro function was not affected by CD40 activation. In addition to previously reported IL-8, MIP-1β and MCP-1, CD40 stimulation in ductal cells produced IL-1β, IFN-γ, TNF-α, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor.

Conclusions/interpretation

CD40 activation in islets and ductal cells produces cytokines/chemokines with a broad-spectrum range of biological functions.

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Title: CD40 activation in human pancreatic islets and ductal cells
Authors: D. Klein
F. Timoneri
H. Ichii
C. Ricordi
R. L. Pastori
Publication date: 01-10-2008
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 10/2008
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-008-1092-y

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