Z Gastroenterol 2019; 57(01): e9
DOI: 10.1055/s-0038-1677061
1. Basic Hepatology (Fibrogenesis, NPC, Transport)
Georg Thieme Verlag KG Stuttgart · New York

LCN2 null mice are sensitive to endoplasmic reticulum stress and unfolded protein responses

E Borkham-Kamphorst
1   RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, Germany
,
E Van de Leur
1   RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, Germany
,
U Haas
1   RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, Germany
,
R Weiskirchen
1   RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Background:

Unfolded protein response (UPR) is an adaptive response, allowing the endoplasmic reticulum (ER) responds to an accumulation of unfolded proteins in its lumen, also known as ER stress. The ER reacts to ER stress through ER transmembrane protein sensors, thus activating intracellular signal transduction pathways. The UPR is interconnected with inflammation through reactive oxygen species production, activation of nuclear factor-kB (NF-kB) and JUN N-terminal kinase (JNK) via inositol-requiring enzyme 1 (IRE1) and induction of acute-phase response. LCN2 is one of the acute phase proteins that are induced under inflammatory conditions and up-regulated during ER stress. We therefore examined the ER stress responses in LCN2-/- condition.

Methods:

We studied UPR in LCN2-/- hepatocytes in which chemical induced ER stress in vitro was induced by tunicamycin (TM) or thapsigargin (TG). Additionally, we explored the UPR of the Lcn2 null mouse livers in acute intoxication and inflammation stages with a single application of lipopolysaccharide or carbon tetrachloride (CCl4).

Results:

The Lcn2-/- hepatocytes reacted with strong UPR to ER stress, as evidenced by significantly increased expression of Grp94, Bip and Chop mRNAs and proteins. TM-and TG-treated hepatocytes activated phospho-p65 NFkB and c-Jun N-terminal kinases (JNK). These pathways are critically activated by stress stimuli and thus play a central role in inflammation and apoptosis. Moreover, compared to wild type cells, Lcn2-/- hepatocytes showed marked increased cytochrome c levels. Additionally, ER stress provoked activation and cleavage of full-length CREBH/CREB3L3 in both, Lcn2-/- and wild type hepatocytes. This factor represents a specific transcription factor to induce systemic inflammatory responses. In vivo, Lcn2 null mice developed stronger UPR in LPS-induced ER stress than the wild type and also showed enhanced UPR in acute CCl4 intoxication compared to the controls.

Conclusion:

Hepatocytes are the major cell types responsible for the highly elevated serum LCN2 protein levels following bacterial infections, whereas elevated amounts of LCN2 protects hepatocytes from ER stress-induced inflammatory responses. These results duly confirm the initial anti-inflammatory protective effect of LCN2 in hepatocytes.