IL-1β induces ER stress in a JNK dependent manner that determines cell death in human pancreatic epithelial MIA PaCa-2 cells

Abstract

The proinflammatory cytokine, IL-1beta (Interleukin-1beta) is a significant determinant of pancreatic apoptosis and cell death that are common characteristics during diabetes. Using human derived pancreatic MIA PaCa-2 cells, we describe one of the underlying molecular mechanisms behind this observation. Incubation of these cells with IL-1beta at doses from 0.5 to 3.0 ng/ml caused significant cell death at 36 h. This was accompanied with marked increases in JNK and p38 phosphorylation together with increased levels of the endoplasmic reticulum (ER) stress markers, namely BiP, CHOP, GADD34, ATF4 and sXBP1. IL-1beta also led to increased phosphorylation of eIF2alpha and all these events could be prevented by pretreatment with the JNK inhibitor, SP600125. A time course study indicated that while IL-1beta mediated JNK phosphorylation was induced as early as 2 h of IL-1beta treatment, induction of the ER stress markers was evident at later time points. IL-1beta stimulated JNK phosphorylation was observed even in the presence of the ER stress inhibitor, 4-phenyl butyrate and the decrease in cell viability was significantly prevented in the presence of the JNK inhibitor. All these suggest that JNK activation is a pre-requisite for ER stress induction and cell death. Reports till date have consistently demonstrated JNK activation as a consequence of ER stress induction by IL-1beta in the pancreas. We show here for the first time that the activation of JNK by IL-1beta is a prelude to the subsequent induction of ER stress and cell death. These therefore suggest that the JNK-ER stress axis is critical in deciding the decreased survival status by IL-1beta in MIA PaCa-2 cells.

Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells

“…It is well established that activation of IRE1 can lead to the phosphorylation of JNK, which plays critical roles in pro-apoptotic pathways (Tabas and Ron, 2011). Meanwhile, research also found that JNK signaling can reciprocally regulate ER stress through an unidentified mechanism (Li et al, 2013; Verma and Datta 2010). In our study, we demonstrated that blocking JNK activity using the inhibitor SP600125 could partially attenuate the increase in CHOP and recover the cell viability, further supported the complicated role of JNK signaling in ER stress (Fig.…”

N-terminal Hydrophobic Amino Acids of Activating Transcription Factor 5 (ATF5) Protein Confer Interleukin 1β (IL-1β)-induced Stabilization

“…Recently, Chan et al (43) showed that proinflammatory cytokines induce ER stress as increased phosphorylation of PERK and eIF2␣, up-regulating ATF4 expression in islets cells. IL-1␤ induces ER stress through JNK, which determines pancreatic cell death (44). Therefore, IL-1␤-induced translational efficiency of ATF5 mRNA could be regulated by PERK-mediated eIF2␣ phosphorylation in a JNK-dependent manner in liver and pancreatic cells.…”

Inflammasomes and Metabolic Disorders: Old Genes in Modern Diseases

“…Second, IL-1β can efficiently evoke the expression of other inflammatory mediators through IL-1R signaling and provides the basis for a self-amplifying cytokine network (Arend et al, 2008 IL-18, and IL-33 families of cytokines). Third, IL-1β induces cell stress, such as ER stress and oxidative stress, both of which have been tightly linked to the pathogenesis of T2D (Cardozo et al, 2005; Verma and Datta, 2010). These findings highlight IL-1β as a potential therapeutic target for the treatment of T2D and small-scale studies employing recombinant IL-1 receptor antagonist (IL-1Ra) provide encouraging data in the treatment of T2D (Larsen et al, 2007).…”