Unfolded protein response (UPR) is an adaptive mechanism allowing the endoplasmic reticulum (ER) to react to an accumulation of unfolded proteins in its lumen, also known as ER stress. The UPR is interconnected with inflammation through several pathways such as reactive oxygen species (ROS) production resulting from the protein folding or alternatively, activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) via IRE1, or induction of acute phase response (APR). Lipocalin 2 (LCN2) is one of the APR proteins induced under inflammatory conditions and up-regulated during ER stress. Upon incubation of Lcn2^−/− and wild type (wt) primary hepatocytes with tunicamycin (TM) or thapsigargin (TG) we found the Lcn2^−/− hepatocytes to react with strong UPR to the ER stress, as evidenced by significantly increased levels of Grp94, Bip and Chop mRNA and protein compared to the wt. TM and TG-treated hepatocytes activated p65 NF-κB and JNK, the pathways that respond to stress stimuli and playing a central role in inflammation and apoptosis, respectively. ER stress further activated and cleaved full-length CREBH/CREB3L3, the hepatocyte specific transcription factor to induce systemic inflammatory responses. Upregulation of the C/EBP homologous protein (CHOP) was very prominent in Lcn2^−/− hepatocytes and sustained until 48 h, resulting in hepatocyte apoptosis as evidenced by increased cleaved caspase 3. We also explored the UPR of the Lcn2 null mouse livers in acute intoxication and inflammation stages with a single application of lipopolysaccharide (LPS) or carbon tetrachloride (CCl₄). The Lcn2 null mice clearly developed stronger UPR in LPS- and CCl₄-induced ER stress compared to the wt. Our findings indicate that the upregulation of LCN2 during ER stress-induced inflammatory responses protects hepatocytes from being overwhelmed by UPR upon liver injury.

未折叠蛋白反应（UPR）是一种适应性机制，允许内质网（ER）对内腔中未折叠蛋白的积累做出反应，也称为ER应激。UPR通过多种途径与炎症相互关联，例如蛋白质折叠产生的活性氧（ROS）产生，或者通过IRE1激活核因子-κB（NF-κB）和c-Jun N端激酶（JNK）。，或诱发急性期反应（APR）。脂蛋白2（LCN2）是在炎症条件下诱导并在ER应激过程中上调的APR蛋白之一。将Lcn2 ^-/-和野生型（wt）原代肝细胞与衣霉素（TM）或thapsigargin（TG）孵育后，我们发现Lcn2 ^-//与wt相比，Grp94，Bip和Chop mRNA和蛋白质的水平显着增加，证明肝细胞与强大的UPR对ER应激反应。经TM和TG处理的肝细胞激活p65NF-κB和JNK，这两种途径分别响应应激刺激并在炎症和细胞凋亡中发挥重要作用。内质网应激进一步激活并切割了全长CREBH / CREB3L3，后者是诱导全身炎症反应的肝细胞特异性转录因子。C / EBP同源蛋白（CHOP）的上调在Lcn2 ^-/-肝细胞中非常明显，并持续到48 h，导致肝细胞凋亡，如裂解的半胱天冬酶3的增加所证明。仅使用脂多糖（LPS）或四氯化碳（CCl ₄）即可在急性中毒和炎症阶段使Lcn2空小鼠肝脏处于急性中毒和炎症状态。与野生型相比，Lcn2无效小鼠在LPS和CCl ₄诱导的ER应激中明显发展出更强的UPR 。我们的发现表明内质网应激诱导的炎症反应中LCN2的上调保护肝细胞免受肝损伤后UPR的压倒。