DcR3 Protects Islet β Cells from Apoptosis through ModulatingAdcyap1andBank1Expression

Abstract

The islet primary nonfunction (PNF) is a serious problem in islet transplantation. In this study, we investigated whether DcR3-secreting transgenic (Tg) islets could reduce PNF. We generated Tg mice expressing human DcR3. The transgenically expressed DcR3 protected islets from IFN-γ plus IL-1β- or TNF-α plus IL-1β-induced dysfunction and apoptosis in vitro. The Tg islets presented significantly reduced PNF after transplantation. Mechanistically, in addition to the known FasL apoptotic pathway, components of two other apoptosis pathways, that is, HVEM/LTβR for the LIGHT pathway and DR3 for the TL1A pathway, were found to be expressed in islets. Recombinant LIGHT- and TL1A-induced islet apoptosis in the absence of the FasL/Fas pathway, as well as DcR3, could block such induction. These results for the first time demonstrated that LIGHT and TL1A were capable of inducing islet apoptosis in addition to FasL, while DcR3 protected the islets by blocking all three apoptosis pathways. By DNA microarray analysis, we discovered that Adcyap was up-regulated >700-fold and Bank1 was down-regulated 50-fold in the cytokine-assaulted Tg islets, compared with WT islets. Forced overexpression of Adcyap1 by plasmid transfection or knockdown of Bank1 expression by small interfering RNA in insulinoma NIT-1 cells protected them from cytokine-triggered apoptosis, indicating that indeed DcR3 protects β cells via the action of these two downstream molecules. This study has revealed novel mechanisms by which DcR3 protects islet survival, and it has identified new therapeutic targets of diabetes.

Trophic Effects of PACAP on Pancreatic Islets: A Mini-Review

“…They found that PACAP mRNA expression levels in DcR3-Tg islets are more than 700-fold higher than those in wild-typeislets after treatment with pro-inflammatory cytokines. In addition, PACAP overexpression protects beta-cells from cytokine-induced apoptosis similar to the DcR3 overexpression, suggesting that PACAP is an inducible downstream factor of DcR3 providing protection from islet apoptosis (Han and Wu 2009). On the other hand, Nakata et al recently showed that endogenous PACAP also contributes to protection from beta-cell dysfunction induced by chronic hyperglycemia and prolonged exposure to high concentrations of free fatty acids (Nakata et al 2010).…”

“…They also demonstrated by quantitative RT-PCR analysis that PACAP suppresses the STZ-increased expression of mRNA of pro-apoptotic factor Noxa and Bax, and increases the mRNA expression of Bcl-2, a pro-survival protein. Han et al have identified several protective molecules against islet dysfunction by investigating the gene expression profile in the isolated islets of mice overexpressing human DcR3 (DcR3-Tg), which is a secreted protein that belongs to the tumor necrosis factor receptor family and suggested as one of trophic factor for beta-cell (Han and Wu 2009). They found that PACAP mRNA expression levels in DcR3-Tg islets are more than 700-fold higher than those in wild-typeislets after treatment with pro-inflammatory cytokines.…”

Shining LIGHT on the metabolic role of the cytokine TNFSF14 and the implications on hepatic IL‐6 production

“…Adding complexity to this signaling cascade, TNFSF14, which may be expressed on the cell surface, secreted or cleaved by metalloproteinases, is considered a promiscuous ligand as it signals via the lymphotoxin‐β receptor (LTβR) and herpesvirus entry mediator (HVEM). The HVEM receptor is highly expressed in visceral adipose tissue and both LTβR and HVEM are expressed in pancreatic beta cells . Interestingly, treatment of human primary adipocytes with TNFSF14 resulted in a potent inhibition of adipocyte differentiation, which suggests that TNFSF14 may be metabolically beneficial although this remains to be comprehensively investigated.…”

“…The HVEM receptor is highly expressed in visceral adipose tissue 23 and both LTbR and HVEM are expressed in pancreatic beta cells. 24 Interestingly, treatment of human primary adipocytes with TNFSF14 resulted in a potent inhibition of adipocyte differentiation, which suggests that TNFSF14 may be metabolically beneficial 25 although this remains to be comprehensively investigated.…”

A decoy receptor 3 analogue reduces localised defects in phagocyte function in pneumococcal pneumonia

“…The decoy receptor DcR3 not only neutralises FasL but also additional TNFSF members LIGHT and TL1A and can modify T-cell activation 24 25. We reasoned if the impaired clearance of bacteria was solely due to FasL deficiency then DcR3 would replicate the gld phenotype in C57BL/6 and lpr mice but have no effect upon gld mice.…”