NF-κB prevents β cell death and autoimmune diabetes in NOD mice

Abstract

Whereas NF-B has potent antiapoptotic function in most cell types, it was reported that in pancreatic ␤ cells it serves a proapoptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of ␤ cell NF-B in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of I B␣ in pancreatic ␤ cells (RIP-mI B␣ mice). ␤ cells of these mice were more susceptible to killing by TNF-␣ plus IFN-␥ but more resistant to IL-1␤ plus IFN-␥ than normal ␤ cells. Similar results were obtained with ␤ cells lacking I B kinase ␤, a protein kinase required for NF-B activation. Inhibition of ␤ cell NF-B accelerated the development of autoimmune diabetes in nonobese diabetic mice but had no effect on glucose tolerance or serum insulin in C57BL/6 mice, precluding a nonphysiological effect of transgene expression. Development of diabetes after transfer of diabetogenic CD4 ؉ T cells was accelerated in RIP-mI B␣/nonobese diabetic mice and was abrogated by anti-TNF therapy. These results suggest that under conditions that resemble autoimmune type 1 diabetes, the dominant effect of NF-B is prevention of TNF-induced apoptosis. This differs from the proapoptotic function of NF-B in IL-1␤-stimulated ␤ cells.

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

“…Diabetes in Atg7 Δβ-cell -ob/ob mice is not related to a previously reported disturbance in glucose profile by RIP-Cre expression itself [23] because the glucose profile and glucose tolerance were normal in our RIP-Cre + colony, as previously reported [30]. Our data are consistent with a previous paper showing a paucity of compensatory beta cell hyperplasia in beta cell-specific autophagy-deficient mice fed a high-fat diet due to increased death and impaired proliferation [31], while diabetes was not observed in these mice.…”

Cytokine-mediated induction of anti-apoptotic genes that are linked to nuclear factor kappa-B (NF-κB) signalling in human islets and in a mouse beta cell line

“…A recent study demonstrated in an inducible transgenic mouse model that beta cell-specific inhibition of NF-κB results in protection against low-dose streptozotocin-induced diabetes [47]. In contrast, accelerated development of autoimmune diabetes has been reported in transgenic NOD mice expressing a repressor of NF-κB in beta cells [48]. Another study observed that inhibition of NF-κB sensitises cultured beta cells to TNF-α-mediated apoptosis [49].…”

Natriuretic Peptide Receptor A as a Novel Anticancer Target

“…Several groups have reported that activation of the NF-nB pathway enhances tumor development and may act primarily in the late stages of tumorigenesis in mouse models of intestinal, liver, and mammary cancer. Inhibition of NF-nB signaling uniformly suppressed tumor development but, depending on the model studied, this salutary effect was attributed to an increase in tumor cell apoptosis, reduced expression of tumor cell growth factors supplied by surrounding stromal cells, or abrogation of a tumor cell dedifferentiation program that is critical for tumor invasion/metastasis (33)(34)(35)(36)(37)(38)(39)(40). The demonstration that pNP73-102 inhibited activation of NF-nB and that NF-nB activation was reduced in the lungs of NPRA À/À mice could represent another additional mechanism underlying its anticancer activity.…”