Pathological roles of ER stress pathway in inflammation

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Endoplasmic reticulum (ER) stress pathway is activated by various stresses to protect ER functions. However, when stresses are severe, ER stress-mediated apoptosis pathway is activated. Therefore, ER stress pathway is involved in the pathogenesis of various diseases. However, the precise molecular mechanisms of the ER stress-related diseases are still unknown. CHOP, a transcription factor of C/EBP family, is involved in ER stress-mediated apoptosis. In this study, we found that ER stress-CHOP pathway is involved in the pathogenesis of inflammation, through non-apoptotic pathway.LPS-induced inflammatory changes and secretion of IL-13 active form in lung were suppressed in Chop knockout mice. IL-1I3 plays crucial roles in the early stage of inflammation. We found that the pro-IL-113 activation process is CHOP-dependent. Therefore, we conclude that ER stress-CHOP pathway regulates inflammatory processes through regulation of cytokine secretion. IL-1I3 is produced as pro-IL-16, which is in … More active and cannot be secreted. Pro-IL-16 is activated by proteolysis with caspase-1 and caspase-11, and then secreted. Caspase 1 is constantly expressed as pro-caspase-1 in inflammatory cells, and caspase-11 is also needed for the activation of caspase-1. Therefore, caspase-11 is a key molecule in the process of IL-13 activation. We showed that induction of caspase-11 in activated macrophages are CHOP-dependent.CHOP has been thought as an apoptosis-inducing molecule. In fact, we previously showed that CHOP-deficient cells are resistant to ER stress-induced apoptosis. However, we found that induction of CHOP do not induce apoptosis in LPS-treated macrophages. In this condition, CHOP activates IL-13 activation process, through induction of caspase-11. We also found that induction of CHOP is delayed, compared to those of ER function-protective molecules, such as BiP, in LPS-treated macrophages. Therefore, we conclude that LPS-induced CHOP does not induce apoptosis, because ER function-protective system is already activated before CHOP expression in immuno-stimulated macrophages. Less