Cytokines and Nitric Oxide in Islet Inflammation and Diabetes

Abstract

Cytokines released by both T lymphocytes and activated macrophages, in particular interleukin-1 (IL-1), have been implicated as immunological effector molecules that both inhibit insulin secretion from the pancreatic beta cell and induce beta-cell destruction. Recent findings have demonstrated that production of the free radical nitric oxide (NO), resulting from the expression of the cytokine-inducible isoform of NO synthase (iNOS), mediates these deleterious effects. The cellular mechanism responsible for inhibition of beta-cell function and destruction by NO involves, in part, inactivation of enzymes specifically localized to the beta-cell mitochondria that contain iron- sulfur centers or clusters. Intraislet release of IL-1 also inhibits beta-cell function by this same cellular mechanism involving the overproduction of NO. In addition, the cytokine, IL-1, induces the co-expression of both iNOS and the cytokine-inducible isoform of cyclooxygenase, COX-2. The expression of COX-2 results in the overproduction of the proinflammatory prostaglandins and thromboxanes. Furthermore, NO produced by iNOS directly stimulates the activities of both constitutive and inducible isoforms of COX, further augmenting the overproduction of these proinflammatory mediators, NO and prostaglandins, which may be important in initiating or maintaining the inflammatory response and destruction of the beta cell associated with autoimmune diabetes.

Punicalagin isolated from Punica granatum husk can decrease the inflammatory response in RAW 264.7 macrophages

“…For this purpose, many fruits as well as pomegranate have been widely used for their antiinflammatory properties (20). Many have reported the anti-inflammatory function of pomegranate in both in vitro and in vivo studies (21,22). Pomegranate juice has been shown to promote antioxidant and antiinflammatory effects by inhibiting oxidative destruction of NO.…”

Gene- and cell-based therapeutics for type I diabetes mellitus

“…While the initial phase of infiltration may not involve b-cell destruction, a number of studies in vivo and in vitro suggest that immune cells become able to render b-cells dysfunctional through the actions of cytokines they produce such as interleukin-1b. [20][21][22][23] Figure 1 illustrates what many believe to be the course of islet inflammation. Many lines of evidence indicate that antigen-presenting cells (APC), especially dendritic cells (DC) are pathologically activated to orchestrate the insulitic process.…”

“…If this is the case, this process can be reversed. [21][22][23][24][74][75][76] Some data strongly suggest that suppression of the activity of the insulitic cells by the induction of immune hyporesponsiveness in clinically diabetic individuals may promote either b-cell neogenesis and/or rescue of the cytokine-suppressed b cells in the insulitic environment. 50,77,78 Inherent in this philosophy is the ability to promote TIDM-specific autoantigen tolerance or TIDM-specific autoantigen immune hyporesponsiveness.…”

Prostaglandin E2 regulates Foxo activity via the Akt pathway: implications for pancreatic islet beta cell dysfunction

“…However, the dosage used in the above experiments did not affect beta cell viability and apoptosis. In addition, insulin-like growth factor 1 (IGF-1) pretreatment reversed the effects of PGE 2 , and wortmannin treatment abolished the preventive effects of IGF-1. Conclusions/interpretation Our observations strongly suggest that PGE 2 can induce pancreatic beta cell dysfunction through the induction of Ptger3 gene expression and inhibition of Akt/Foxo phosphorylation without impacting beta cell viability.…”

“…Pancreatic beta cell . PGE 2 Abbreviations CA-Akt constitutively active Akt COX cyclooxygenase FBS fetal bovine serum FKHR forkhead transcription factor Foxo1 FKHRL1 forkhead transcription factor Foxo3a Foxo forkhead box 'Other' GSIS glucose-stimulated insulin secretion IGF-1 insulin-like growth factor-1 PGE 2 prostaglandin E 2 PI3K phosphatidylinositol 3-kinase PTGER prostaglandin E receptor RPMI-1640 Roswell Park Memorial Institute-1640 Introduction Types 1 and 2 diabetes mellitus are characterised by autoimmune destruction and functional impairment of insulin-secreting beta cells in the pancreatic islets of Langerhans [1][2][3]. Although the initial events leading to the development of diabetes mellitus are not well characterised, proinflammatory prostaglandins, including prostaglandin E 2 (PGE 2 ) appear to play an important role.…”