CD40 activation in human pancreatic islets and ductal cells

Diabetologia. 2008 Oct;51(10):1853-61. doi: 10.1007/s00125-008-1092-y. Epub 2008 Jul 26.


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-1beta) and monocyte chemoattractant protein-1 (MCP-1) through nuclear factor-kappaB 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-1beta and MCP-1, CD40 stimulation in ductal cells produced IL-1beta, IFN-gamma, TNF-alpha, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD40 Antigens / genetics
  • CD40 Antigens / metabolism*
  • CD40 Antigens / physiology
  • CD40 Ligand / genetics
  • CD40 Ligand / metabolism
  • CD40 Ligand / physiology
  • Cell Survival
  • Chemokine CXCL1 / metabolism
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Pancreatic Ducts / cytology
  • Pancreatic Ducts / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Young Adult


  • CD40 Antigens
  • Chemokine CXCL1
  • Chemokines
  • Cytokines
  • CD40 Ligand