IL‐1β receptor blockade protects islets against pro‐inflammatory cytokine induced necrosis and apoptosis

Abstract

Pro-inflammatory cytokines (PIC) impair islet viability and function by activating inflammatory pathways that induce both necrosis and apoptosis. The aim of this study was to utilize an in vitro rat islet model to evaluate the efficacy of a clinically approved IL-1 receptor antagonist (Anakinra) in blocking PIC induced islet impairment. Isolated rat islets were cultured for 48h ± PIC (IL-1β, IFNγ, and TNFα and ±IL-1ra then assayed for cellular integrity by flow cytometry, MAPK phosphorylation by proteome array, and gene expression by RT-PCR. Nitric oxide (NO) release into the culture media was measured by Griess reaction. Islet functional potency was tested by glucose stimulated insulin secretion (GSIS) and by transplantation into streptozotocin-induced diabetic NOD.scid mice. Rat islets cultured with PIC upregulated genes for NOS2a, COX2, IL6, IL1b, TNFa, and HMOX1. IL-1ra prevented the PIC induced upregulation of all of these genes except for TNFa. Inhibition of PIC induced iNOS by NG-monomethyl-L-arginine (NMMA) only blocked the increased expression of HMOX1. IL-1ra completely abrogated the effects of PIC with respect to NO production, necrosis, apoptosis, mitochondrial dysfunction, GSIS, and in vivo potency. IL-1ra was not effective at preventing the induction of necrosis or apoptosis by exogenous NO. These data demonstrate that Anakinra is an effective agent to inhibit the activation of IL-1β dependent inflammatory pathways in cultured rat islets and support the extension of its application to human islets in vitro and potentially as a post transplant therapy.

Thioredoxin-1 Attenuates Early Graft Loss after Intraportal Islet Transplantation in Mice

“…Corroborating our findings, Yoshioka et al and Billiet et al have reported that TRX could regulate the activation of NF-kB, followed by the suppression of IL-1b production [17,33]. It has been reported that pancreatic islets are highly sensitive to proinflammatory cytokines such as IL-1b [34][35][36]. Montolio et al [37] reported that IL-1b mRNA in the transplanted islets was upregulated immediately after islet infusion, and that IL-1b played a crucial role in the extensive b-cell death found in the initial days after islet transplantation.…”

Role of the TLR signaling molecule TRIF in β-cell function and glucose homeostasis

“…12 Numerous reports indicate that TLR activation can lead to peripheral insulin resistance as well as b-cell dysfunction and death. [28][29][30][31][32] Our surprising observations indicate that although increased TLR signaling may be harmful to the b-cell during inflammation, signaling through TRIF is essential for maintaining glucose homeostasis under normal conditions. We therefore propose a previously unrecognized role for TRIF in glucose homeostasis and normal b-cell function.…”

Toll-like receptors, the NLRP3 inflammasome, and interleukin-1β in the development and progression of type 1 diabetes

“…Treating rat islet cells with IL1-ra protects against proinflammatory cytokine (IL1β, tumor necrosis factor-α, and interferon-γ)-induced cell death. In addition, mice given rat islets pretreated with proinflammatory cytokines were unable to restore glycemic control, whereas mice treated with IL1-ra under the same conditions were able to restore normoglycemia for the 28-d experiment (64). Further, although another group found that pretreatment of NOD mice with IL1-ra prevented hyperglycemia but not insulitis (65), another group reported that previously diabetic NOD mice that received an islet transplantation and were then treated with IL1-ra remained euglycemic while they received the antagonist, whereas hyperglycemia recurred in control animals within 6 d after transplantation (66).…”