JNK activation by ER stress was dependent on the IRE1 kinase domain [60]. In mouse embryonic fibroblasts, ER stress caused by thapsigargin, activated p38

MAPK and JNK in a PERK-dependent manner [64]. NF-κB lies inactive in the cytoplasm due to direct interaction with its inhibitor IκB. Once phosphorylated by IκB kinase (IKK), IκB is degraded and releases active selleck chemical NF-κB, which then translocates to the nucleus and induces transcription of several genes, including pro-inflammatory cytokines (reviewed by [65]). Activation of NF-κB by the UPR pathway occurs by at least two distinct mechanisms. Once activated by ER stress, the kinase domain of IRE1 interacts with TRAF2 and IKK, leading to degradation of IκB, activation of NF-κB, and TNF-α synthesis by several cell types [63]. Alternatively, PERK phosphorylates eIF2α, inhibiting IκB translation. As the half-life of IκB is much shorter than the one of NF-κB, an accumulation of free NF-κB occurs, followed by nuclear translocation and transcription activation [61, 62] (Fig. 2). The production of type I interferons (IFNs) also seems

to be mediated by the UPR pathway [66]. A synergic effect was observed when cells where stimulated with ER stressors and pattern recognition receptors (PRRs) agonists. Induction of IFN-β by ER stress was dependent on XBP-1 and the TRIF/IRF3 pathway, downstream to several PRRs such as TLR4 and MDA5 [66]. In accordance to this, a cis-enhancer region that interacts with XBP-1s STA-9090 mouse was found 6.1 kb downstream IFNB1, which codes for IFN-β. One plausible explanation is that after LPS stimulation and consequent ER stress, eltoprazine XBP-1s binds to this enhancer and recruits IRF3 and CBP. Through a chromatin loop, these factors are brought closer to the IFNB1 promoter region, resulting in more efficient transcription machinery recruitment [67]. ER stress also plays an important role on acute phase responses [68]. CREBH is a liver specific transcription factor

activated upon ER stress. CREBH is found anchored in ER membrane and, once activated, it translocates to the Golgi complex. Proteolytic cleavage by S1P and S2P releases an active N-terminal fragment that translocates to the nucleus, where together with ATF6, regulates transcription of acute phase genes coding for proteins such as C-reactive protein and serum amyloid P component. Although CREBH does not contribute directly to the activation or regulation of the UPR pathway, it is activated by ER stress and is necessary for acute phase response [68]. Recently, it was shown that TLR signalling activates the IRE1/XBP-1 axis and that this loop is crucial for host defense [69]. TLRs are well-conserved receptors that recognize pathogen-associated molecular patterns and danger signals (reviewed by [70]).