CD40-CD40 ligand interaction activates proinflammatory pathways in pancreatic islets.
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 beta-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 beta-cells responded to CD40L interaction by secreting interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and macrophage inflammatory protein (MIP)-1beta, the latter a chemokine first reported to be produced by islets. Induction of IL-8 and MIP-1beta was confirmed at the transcriptional level by quantitative RT-PCR. MIP-1beta expression in beta-cells was verified by double-immunofluorescence staining. CD40-CD40L interaction activates extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB 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 beta-cells could be activated in vivo, inducing proinflammatory responses contributing to early islet graft loss after transplantation.
Barbé-Tuana
Florencia M
FM
Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Klein
Dagmar
D
Ichii
Hirohito
H
Berman
Dora M
DM
Coffey
Lane
L
Kenyon
Norma S
NS
Ricordi
Camillo
C
Pastori
Ricardo L
RL
D000328:Adult; D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054407:Chemokine CCL4; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D008252:Macaca fascicularis; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology; D025941:Protein Interaction Mapping; D048490:raf Kinases / Q000502:physiology
D019013:CD40 Antigens; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases