1. ER stress-induced inflammation: does it aid or impede disease progression? 
Abhishek D. Garg, Agnieszka Kaczmarek, Olga Krysko, Peter Vandenabeele, Dmitri V. Krysko, Patrizia Agostinis 
Trends in Molecular Medicine 
Volume 18, Issue 10, Pages (October 2012)
DOI: /j.molmed
Copyright © 2012 Elsevier Ltd Terms and Conditions

2. Figure 1
Schematic representation of IRE1α-mediated, ATF6-mediated, and PERK-mediated inflammatory transcriptional program. Following ER stress, PERK activates NF-κB via translational attenuation. The activated PERK-eIF2α arm causes translational arrest, which leads to decreased levels of IκB protein and a consequent increase in the ratio of NF-κB to IκB. This change in the ratio causes the release of NF-κB protein, which then carries out its proinflammatory transcriptional role in the nucleus [96]. Similarly, the PERK-eIF2α arm also carries out immunomodulation via CHOP, which activates transcription of the gene for IL-23, a proinflammatory cytokine [97]. PERK-eIF2α causes CHOP production via ATF4, whose mRNA is transcribed only under conditions of translational attenuation. Interestingly, it was recently observed that ER stress-induced CHOP activation can also negatively regulate the inflammatory responses by modulating NF-κB as well as JNK (leading to modulation of downstream AP-1 activity) [98]. By contrast, ER stress can also cause the activation of IRE1α, which can then bind the tumor-necrosis factor (TNF)-α-receptor-associated factor 2 (TRAF2). Importantly, this IRE1α–TRAF2 complex can activate IκB kinase (IKK). Activated IKK then causes IκB degradation, thereby freeing NF-κB to transcribe the proinflammatory gene program [11,30]. Similarly, the IRE1α–TRAF2 complex has also been shown to activate the JNK protein, which consequently phosphorylates and activates AP-1 (which in turn transcribes its own inflammatory gene program) [99]. Finally, under conditions of ER stress, ATF6 can leave the ER and reach the Golgi complex, where it can undergo ‘regulated intramembrane proteolysis’ (RIP). During RIP, ATF6 is cleaved by local site 1 and site 2 proteases (S1P and S2P) [6,100]. The activated ATF6 fragments form homodimers and transcribe acute-phase response (APR)-associated genes, such as those encoding acute-phase proteins (APPs) [6,101].
Trends in Molecular Medicine  , DOI: ( /j.molmed )
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3. Figure 2
ER stress-induced inflammation in health and disease. Crosstalk between inflammation and ER stress can either aid or impede the pathogenesis and/or progression of certain diseases. For instance, ER stress-induced inflammation and even ER stress on its own, can affect pancreatic β cells as well as adipocytes and macrophages, thereby aiding the progression of type 2 diabetes and obesity, respectively. Obesity-associated inflammation can further aid type 2 diabetes progression by suppressing insulin receptor signaling. Similarly, ER stress-induced inflammation can affect intestinal epithelial cells, Paneth cells, and goblet cells, possibly aiding the progression of inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis. Furthermore, ER stress-induced inflammation has been implicated in aiding the progression of cystic fibrosis and cigarette smoke-induced chronic obstructive pulmonary disease, both of which are chronic inflammatory airway diseases. However, the link between ER stress-induced inflammation and cancer is not as simple, although ER stress-induced inflammation has been shown to aid tumorigenesis, it has also been shown to impede tumorigenesis by inducing immunogenic cell death-based antitumor immunity.
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4. Figure 3
A model for pro- and antitumorigenic effects of ER stress-mediated inflammation associated with the tumor microenvironment or induced by therapeutics. A typical tumor microenvironment is usually associated with ER stress [73]. (a) ER stress within cancer cells can cause activation of NF-κB and AP-1, which in turn can cause the cancer cells to produce tumor-promoting cytokines [3,65]. (b) As immune cells constantly infiltrate tumor tissues [3,81], ER stress induction within the tumor microenvironment can affect both immune cells and cancer cells. Induction of ER stress in immune cells causes them to secrete even more tumor-promoting cytokines [5,15]. (c) ER stress on tumor-infiltrating immune cells that transport large protein cargos through their ER and are thus sensitive to ER stress, such as B lymphocytes [6], can compromise antitumor immunity. (d) This scenario can be further complicated by the effects of immune cells on tumor cells. For instance, expression of cytokines such as interferon (IFN)-γ and interleukin (IL)-1β [102,103], TNF, and IL-6 [101] by immune cells can generate further ER stress in cancer cells by activation of various UPR components, such as PERK, IRE1α, ATF6, and CREBH [6,101]. This cytokine-induced ER stress might also induce production of tumor-promoting cytokines. By contrast, ER stress can also exert antitumorigenic effects. (e) More specifically, associated with therapy or the microenvironment, ER stress-induced acute-phase response (APR) can lead to increased infiltration of neutrophils into tumors (neutrophilia), so that neutrophils can mediate tumor-controlling inflammation. (f) Alternatively, ER stress caused by induction of reactive oxygen species (ROS) by certain chemotherapeutic agents, radiotherapy, and photodynamic therapy could cause the cancer cells to undergo immunogenic cell death. This immunogenic sub-routine of dying can help to prime dendritic cells (DCs) for tumor antigens, and these ‘primed DCs’ could then exert potent antitumor immune responses that reduce or control tumorigenesis.
Trends in Molecular Medicine  , DOI: ( /j.molmed )
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