HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barbé-Tuana, F. M. Articles by Pastori, R. L. Search for Related Content PubMed PubMed Citation Articles by Barbé-Tuana, F. M. Articles by Pastori, R. L. Social Bookmarking                What's this?

CD40–CD40 Ligand Interaction Activates Proinflammatory Pathways in Pancreatic Islets

From the Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida

Address correspondence and reprint requests to R.L. Pastori, PhD, Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, 1450 NW 10th Ave., Miami, FL 33136. E-mail: rpastori{at}med.miami.edu

Abbreviations: APC, antigen-presenting cell; 7-AAD, 7-aminoactinomycin D; ERK, extracellular signal–regulated kinase; ICAM, intercellular adhesion molecule; IB, inhibitor of B; IL, interleukin; IFN-, -interferon; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; MEK, mitogen extracellular kinase; MIP, macrophage inflammatory protein; NF, nuclear factor; NHP, nonhuman primate; Th1, T-helper 1; TNF, tumor necrosis factor

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 ß-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 ß-cells responded to CD40L interaction by secreting interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and macrophage inflammatory protein (MIP)-1ß, the latter a chemokine first reported to be produced by islets. Induction of IL-8 and MIP-1ß was confirmed at the transcriptional level by quantitative RT-PCR. MIP-1ß expression in ß-cells was verified by double-immunofluorescence staining. CD40-CD40L interaction activates extracellular signal–regulated kinase 1/2 and nuclear factor-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 ß-cells could be activated in vivo, inducing proinflammatory responses contributing to early islet graft loss after transplantation.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S Danese, F Scaldaferri, S Vetrano, T Stefanelli, C Graziani, A Repici, R Ricci, G Straface, A Sgambato, A Malesci, et al. Critical role of the CD40 CD40-ligand pathway in regulating mucosal inflammation-driven angiogenesis in inflammatory bowel disease Gut, September 1, 2007; 56(9): 1248 - 1256. [Abstract] [Full Text] [PDF]