CD40-CD40 ligand interaction activates proinflammatory pathways in pancreatic islets

Florencia M. Barbé-Tuana, Dagmar Klein, Hirohito Ichii, Dora M. Berman, Lane Coffey, Norma S. Kenyon, Camillo Ricordi, Ricardo L. Pastori

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Pancreatic islet transplantation is becoming an alternative to insulin therapy in patients suffering from brittle type 1 diabetes. A major obstacle to the procedure is the early graft loss caused by nonspecific inflammation at the site of implantation. We recently discovered that CD40, a member of tumor necrosis factor (TNF) receptor family, is expressed in pancreatic β-cells. CD40 expression in nonhematopoietic cells is generally associated with inflammation. Therefore, we investigated the potential proinflammatory role of CD40 in human and nonhuman primate islets. Islet β-cells responded to CD40L interaction by secreting interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and macrophage inflammatory protein (MIP)-1β, the latter a chemokine first reported to be produced by islets. Induction of IL-8 and MIP-1β was confirmed at the transcriptional level by quantitative RT-PCR. MIP-1β expression in β-cells was verified by double-immunofluorescence staining. CD40-CD40L interaction activates extracellular signal-regulated kinase 1/2 and nuclear factor-{kappa}B pathways in insulinoma NIT-1 cells, and inhibitors of either pathway suppress cytokine/chemokine production in islets. Moreover, ligation of CD40 receptor upregulates intercellular adhesion molecule-1, associated with inflammation, at both transcriptional and translational levels. Our results in vitro indicate that the CD40 receptor expressed by β-cells could be activated in vivo, inducing proinflammatory responses contributing to early islet graft loss after transplantation.

Original languageEnglish (US)
Pages (from-to)2437-2445
Number of pages9
JournalDiabetes
Volume55
Issue number9
DOIs
StatePublished - Sep 1 2006

Keywords

  • 7-AAD
  • 7-aminoactinomycin D
  • Antigen-presenting cell
  • APC
  • ERK
  • Extracellular signal-regulated kinase
  • ICAM, intercellular adhesion molecule
  • IFN-{gamma},{gamma}-interferon
  • IL, interleukin
  • Inhibitor of {kappa}B
  • I{kappa}B
  • mAb, monoclonal antibody

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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