Molecules and Cells

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Fig. 3.

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Fig. 3. ER stress-induced signaling pathways play important roles in inflammatory responses. (A) Increased inflammation due to ER stress; ER stress has been implicated in the pathogenesis of inflammatory and autoimmune diseases, such as obesity, diabetes, atherosclerosis, myositis, and inflammatory bowel disease. ER stress induces inflammatory responses by activating UPR transcription factors, such as XBP1s, ATF6, and CREBH. These transcription factors upregulate the pro-inflammatory cytokines IL-1β, TNF-α, and IFN-γ, and the acute phase proteins SAP and CRP. (B) Activation of inflammatory signaling by the UPR; ER stress induces interactions between UPR components and inflammatory signaling cascades. Activated IRE1 interacts with IKK via the adaptor protein TRAF2 and induces NF-κB by initiating proteasomal degradation of IκBα. Phosphorylation of eIF2α inhibits the translation of IκBα and lowers expression levels, thereby activating NF-κB. IRE1 also activates JNK by binding TFAF2 at its cytoplasmic region. Activation of NF-κB and AP-1 by ER stress upregulates inflammatory genes, and is considered a mechanism for inducing inflammatory responses. (C) Activation of the UPR by inflammation; pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, induce ER stress and activate the UPR. LPS also increases the expression of inflammatory cytokines and ER stress-related genes. After inflammatory activation, the UPR causes excessive inflammation and induces apoptosis, thus exacerbating disease conditions. CREBH, cAMP responsive element binding protein H; SAP, serum amyloid P-component; CRP, C-reactive protein; IKK, IκB kinase; TRAF2, TNF-α receptor associated factor 2; IκB, inhibitor of κB; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide.
Mol. Cells 2018;41:705~716
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