Modulation of the peroxiredoxin system by cytokines in insulin-producing RINm5F cells: Down-regulation of PRDX6 increases susceptibility of beta cells to oxidative stress

Abstract

Peroxiredoxins are a family of six antioxidant enzymes (PRDX1-6), and may be an alternative system for the pancreatic beta cells to cope with oxidative stress. This study investigated whether the main diabetogenic pro-inflammatory cytokines or the anti-inflammatory cytokine IL-4 modulate PRDXs levels and putative intracellular pathways important for this process in the insulin-producing RINm5F cells. RINm5F cells expressed significant amounts of PRDX1, PRDX3 and PRDX6 enzymes. Only PRDX6 was modulated by cytokines, showing both mRNA and protein down-regulation following incubation of RINm5F cells with TNF-alpha and IFN-gamma but not with IL-1beta. Separately IFN-gamma or TNF-alpha decreased PRDX6 protein but not mRNA levels. The blockage of the JNK signalling and of the calpains and proteasome proteolysis systems restored PRDX6 protein levels. IL-4 alone did not modulate PRDXs levels. However, pre/co-incubation with IL-4 substantially prevented the decrease in PRDX6 induced by pro-inflammatory cytokines. Knockdown of PRDX6 increased susceptibility of RINm5F cells to the deleterious effects of pro-inflammatory cytokines and to oxidative stress. These results show that, from the PRDXs significantly expressed in RINm5F cells, only PRDX6 is modulated by the diabetogenic cytokines IFN-gamma and TNF-alpha. This PRDX6 down-regulation depends on the calpain and proteasome systems and JNK signalling. PRDX6 is an important enzyme for protection against oxidative stress and the interaction between pro- and anti-inflammatory cytokines might be important to determine the antioxidant capacity of the cells.

The impact of anti-inflammatory cytokines on the pancreatic β-cell

“…Finally, one recent study has revealed that pro-inflammatory cytokines reduced the expression of peroxiredoxin 6 in clonal b-cells, thereby rendering these cells more vulnerable to oxidative stress. 84 IL-4 reversed this effect. Taken together (and allowing for the fact that not all data are fully concordant) it can be argued that anti-inflammatory cytokines are likely to inhibit IL-1b induced NO production upstream of iNOS expression in b-cells; conceivably by modulation of NFkB activation.…”

Exercise increases pancreatic β‐cell viability in a model of type 1 diabetes through IL‐6 signaling

“…Similarly, a crosstalk between the Janus kinase (JAK)/STAT and NF‐κB pathways has been reported, showing that inflammatory cytokine signaling could impair IL‐6‐induced JAK/STAT activation (54). In addition, IL‐4, another anti‐inflammatory cytokine, which also signals via JAK/STAT, protects pancreatic β cells from the decrease in antioxidant enzyme peroxiredoxin 6, provoked by inflammatory cytokines (55). However, this issue still needs to be addressed for a better understanding of the cross‐talk among these cytokine signaling pathways in pancreatic β cells.…”

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

“…Inflammation is a main factor leading to diabetes and its associated complications (19). A recent study (42) in b-cells demonstrated that mRNA and protein expression of PRDX6 2/2 mice. Values are expressed as mean 6 SE.…”