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.
Keywords: ER stress; Hepatocytes; Inflammation; Lipocalin 2; Liver; Unfolded protein response.
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