Liver is the major source of elevated serum lipocalin‐2 levels after bacterial infection or partial hepatectomy: A critical role for IL‐6/STAT3. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Xu, Ming‐Jiang; Feng, Dechun; Wu, Hailong; Wang, Hua; Chan, Yvonne; Kolls, Jay; Borregaard, Niels; Porse, Bo; Berger, Thorsten; Mak, Tak W.; Cowland, Jack B.; Kong, Xiaoni; Gao, Bin
• Is Part Of: Hepatology. Volume 61:Issue 2(2015:Feb.)
• Page Start: 692
• Page End: 702
• Publication Date: 2015-02
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.27447
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Lipocalin‐2 (LCN2) was originally isolated from human neutrophils and termed neutrophil gelatinase‐associated lipocalin (NGAL). However, the functions of LCN2 and the cell types that are primarily responsible for LCN2 production remain unclear. To address these issues, hepatocyte‐specific <italic>Lcn2</italic> knockout (<italic>Lcn2</italic><sup>Hep–/–</sup>) mice were generated and subjected to bacterial infection (with <italic>Klesbsiella pneumoniae</italic> or <italic>Escherichia coli)</italic> or partial hepatectomy (PHx). Studies of <italic>Lcn2</italic><sup>Hep–/–</sup> mice revealed that hepatocytes contributed to 25% of the low basal serum level of LCN2 protein (∼62 ng/mL) but were responsible for more than 90% of the highly elevated serum LCN2 protein level (∼6, 000 ng/mL) postinfection and more than 60% post‐PHx (∼700 ng/mL). Interestingly, both <italic>Lcn2</italic><sup>Hep–/–</sup> and global <italic>Lcn2</italic> knockout (<italic>Lcn2</italic><sup>–/–</sup>) mice demonstrated comparable increases in susceptibility to infection with <italic>K. pneumoniae</italic> or <italic>E. coli</italic>. These mice also had increased enteric bacterial translocation from the gut to the mesenteric lymph nodes and exhibited reduced liver regeneration after PHx. Treatment with interleukin (IL)‐6 stimulated hepatocytes to produce LCN2 <italic>in vitro</italic> and <italic>in vivo</italic>. Hepatocyte‐specific ablation of the IL‐6 receptor or <italic>Stat3</italic>, a major downstream effector of IL‐6, markedly abrogated LCN2 elevation <italic>in vivo</italic>. Furthermore, chromatin immunoprecipitation (ChIP) assay revealed that STAT3 was recruited to the promoter region of the <italic>Lcn2</italic> gene upon STAT3 activation by IL‐6. <italic>Conclusion</italic>: Hepatocytes are the major cell type responsible for LCN2 production after bacterial infection or PHx, and this response is dependent on IL‐6 activation of the STAT3 signaling pathway. Thus, hepatocyte‐derived LCN2 plays an important role in inhibiting bacterial infection and promoting liver regeneration. (H<sc>epatology</sc> 2015;61:692‐702)</p> </abstract>