CD40-CD40 ligand interaction activates proinflammatory pathways in pancreatic islets

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

Research output: Contribution to journalArticle

44 Citations (Scopus)

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

Fingerprint

CD40 Ligand
Islets of Langerhans
Macrophage Inflammatory Proteins
Inflammation
Interleukin-8
Chemokines
Transplants
Islets of Langerhans Transplantation
Insulinoma
Mitogen-Activated Protein Kinase 3
NF-kappa B
Chemokine CCL2
Tumor Necrosis Factor Receptors
Mitogen-Activated Protein Kinase 1
Intercellular Adhesion Molecule-1
Type 1 Diabetes Mellitus
Primates
Fluorescent Antibody Technique
Ligation
Interleukin-6

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

Cite this

CD40-CD40 ligand interaction activates proinflammatory pathways in pancreatic islets. / Barbé-Tuana, Florencia M.; Klein, Dagmar; Ichii, Hirohito; Berman-Weinberg, Dora; Coffey, Lane; Kenyon, Norma S; Ricordi, Camillo; Pastori, Ricardo.

In: Diabetes, Vol. 55, No. 9, 01.09.2006, p. 2437-2445.

Research output: Contribution to journalArticle

Barbé-Tuana, Florencia M. ; Klein, Dagmar ; Ichii, Hirohito ; Berman-Weinberg, Dora ; Coffey, Lane ; Kenyon, Norma S ; Ricordi, Camillo ; Pastori, Ricardo. / CD40-CD40 ligand interaction activates proinflammatory pathways in pancreatic islets. In: Diabetes. 2006 ; Vol. 55, No. 9. pp. 2437-2445.
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AU - Barbé-Tuana, Florencia M.

AU - Klein, Dagmar

AU - Ichii, Hirohito

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AU - Coffey, Lane

AU - Kenyon, Norma S

AU - Ricordi, Camillo

AU - Pastori, Ricardo

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N2 - 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.

AB - 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.

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