Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents

Abstract

Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta cells. Isletinfiltrating leukocytes secrete cytokines such as IL-1␤ and IFN-␥, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-B is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-B in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-B protein inhibitor (⌬NI B␣), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the ⌬NI B␣ protein were resistant to the deleterious effects of IL-1␤ and IFN-␥, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo, where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-B is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.apoptosis ͉ cytokine ͉ diabetes ͉ transgenic mice ͉ insulin

Cross-talk between the unfolded protein response and nuclear factor-κB signalling pathways regulates cytokine-mediated beta cell death in MIN6 cells and isolated mouse islets

“…PBA potentiates cytokine-stimulated changes in NFκB-regulated gene expression Because NFκB activation may play an important regulatory role in cytokine-mediated beta cell death [5,6], we tested whether PBA treatment affected NFκB-regulated gene expression. In control MIN6 cells, treatment with cytokines for 24 h resulted in increased mRNA expression of genes known to be regulated by NFκB, namely iNos (Fig.…”

“…Simultaneous activation of NFκB in a beta cell can be influenced by this increased proteasome activity because of the continual loss of IκBα protein. Although NFκB signalling is pro-survival in immune cells, it can be apoptotic in beta cells [6]. Hence, a switch in the balance of the UPR to favour NFκB activation can lead to potentiated beta cell death.…”

“…Nuclear factor-κB (NFκB) has been identified as a key regulator of transcription factors and gene networks controlling cytokine-induced beta cell dysfunction and death [4][5][6]. NFκB is formed as a homo-or hetero-dimer comprising p50, p52 and p65 subunits, and is sequestered in the cytoplasm of unstimulated cells as an inactive complex with inhibitor of κB-α (IκBα) protein [7].…”

Involvement of the RNA-binding protein ARE/poly(U)-binding factor 1 (AUF1) in the cytotoxic effects of proinflammatory cytokines on pancreatic beta cells

“…The transcription factor NFκB contributes to cytokine-mediated beta cell dysfunction and to the development of type 1 diabetes. Indeed, Eldor and collaborators showed that mice producing an NFκB repressor are protected from diabetes induced by streptozotocin injections [42]. Recently, inhibition of AUF1 was reported to prevent lipopolysaccharideinduced NFκB signalling in monocytes and macrophages [43].…”

Is ARE/poly(U)-binding factor 1 (AUF1) a new player in cytokine-mediated beta cell apoptosis?

“…It has been extensively shown that NFκB has a mainly pro-inflammatory and pro-apoptotic role in beta cells [17][18][19][20], but long-term prevention of NFκB activation in beta cells from NOD mice accelerates the disease [21]. This is probably due to the inhibition of the production of NFκB-dependent anti-apoptotic proteins, such as the X-linked inhibitor of apoptosis protein (XIAP) and A20 [21,22].…”