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Zinc regulates the acute phase response and serum amyloid A production in response to sepsis through JAK-STAT3 signaling.

ABSTRACT: Sepsis rapidly activates the host inflammatory response and acute phase response. Severe sepsis, complicated by multiple organ failure, is associated with overwhelming inflammation and high mortality. We previously observed that zinc (Zn) deficiency significantly increases mortality in a mouse model of polymicrobial sepsis due to over-activation of the inflammatory response. In order to identify potential mechanisms that account for Zn-responsive effects, we generated whole exome expression profiles from the lung tissue of septic mice that were maintained on Zn modified diets. Based on systems analysis, we observed that Zn deficiency enhances the acute phase response and particularly the JAK-STAT3 pathway, resulting in increased serum amyloid A production. In vitro studies of primary hepatocytes and HepG2 cells substantiated that Zn-deficiency augments serum amyloid A production through up-regulation of the JAK-STAT3 and NF-?B pathways. In contrast, Zn inhibited STAT3 activation through the up-regulation of SHP1 activity. Collectively, these findings demonstrate that Zn deficiency enhances the acute phase response through up-regulation of the JAK-STAT3 pathway, thereby perpetuating increased inflammation that may lead to increased morbidity and mortality in response to sepsis.

SUBMITTER: Liu MJ

PROVIDER: S-EPMC3986341 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Zinc regulates the acute phase response and serum amyloid A production in response to sepsis through JAK-STAT3 signaling.

Liu Ming-Jie MJ Bao Shengying S Napolitano Jessica R JR Burris Dara L DL Yu Lianbo L Tridandapani Susheela S Knoell Daren L DL

PloS one 20140414 4

Sepsis rapidly activates the host inflammatory response and acute phase response. Severe sepsis, complicated by multiple organ failure, is associated with overwhelming inflammation and high mortality. We previously observed that zinc (Zn) deficiency significantly increases mortality in a mouse model of polymicrobial sepsis due to over-activation of the inflammatory response. In order to identify potential mechanisms that account for Zn-responsive effects, we generated whole exome expression prof ...[more]

PMID: 24732911

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Project description:BackgroundThe study of the immune microenvironment in prostate cancer (PRAD) has brought new opportunities for the current traditional treatment regimens. Therefore, our goal is to develop a universal immunodiagnostic marker to improve patient survival.MethodsBioinformatics analysis: We collected 591 samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts and evaluated the abundance and distribution of immune cell members in the PRAD expression profile matrix in the mixed cell population by CIBERSORT, ESTIMATE, single-sample gene set enrichment analysis (ssGSEA), and other methods. The target genes related to PRAD immune microenvironment and tumor mutation load were obtained by overlap analysis and verified by pan-cancer analysis. Cell experiment: The cell transfection scheme was designed, and the experiment was divided into three groups: overexpressing lactoferrin (LTF) group, empty plasmid group, and control group. After obtaining cells in each group, the gene and protein expression levels of LTF and signal transduction of signal transducer and activator of transcription 3 (STAT3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the above three groups were detected by real-time PCR and Western blot, respectively. Finally, the level of GM-CSF secretion in the three groups was detected by ELISA.ResultsMacrophages, resting mast cells, and plasma cells play an important role in PRAD immune microenvironment. In addition, high tumor mutation load [tumor mutational burden (TMB)] was positively correlated with lymph node metastasis in patients with PRAD. As the core gene of the PRAD immune microenvironment, the low expression of LTF in PRAD promotes the occurrence of immunodeficiency, PRAD, and the enrichment of the Janus kinase (JAK)/STAT3 signal pathway. Through cell experiments, it was found that the content of LTF mRNA and protein increased significantly, while the content of STAT3 and GM-CSF mRNA and protein decreased significantly in the overexpressed LTF group. The level of GM-CSF in the supernatant of cell culture was significantly decreased in the overexpression group of LTF.ConclusionThe core gene we proposed is one of the most promising biomarkers to improve the overall survival rate of PRAD and provides an important theoretical basis for the study of the mechanism of the LTF-mediated JAK/STAT3 pathway in PRAD.

Project description:Neuropathic pain, a debilitating pain condition, is a common consequence of damage to the nervous system. Optimal treatment of neuropathic pain is a major clinical challenge because the underlying mechanisms remain unclear and currently available treatments are frequently ineffective. Emerging lines of evidence indicate that peripheral nerve injury converts resting spinal cord glia into reactive cells that are required for the development and maintenance of neuropathic pain. However, the mechanisms underlying reactive astrogliosis after nerve injury are largely unknown. In the present study, we investigated cell proliferation, a critical process in reactive astrogliosis, and determined the temporally restricted proliferation of dorsal horn astrocytes in rats with spinal nerve injury, a well-known model of neuropathic pain. We found that nerve injury-induced astrocyte proliferation requires the Janus kinase-signal transducers and activators of transcription 3 signalling pathway. Nerve injury induced a marked signal transducers and activators of transcription 3 nuclear translocation, a primary index of signal transducers and activators of transcription 3 activation, in dorsal horn astrocytes. Intrathecally administering inhibitors of Janus kinase-signal transducers and activators of transcription 3 signalling to rats with nerve injury reduced the number of proliferating dorsal horn astrocytes and produced a recovery from established tactile allodynia, a cardinal symptom of neuropathic pain that is characterized by pain hypersensitivity evoked by innocuous stimuli. Moreover, recovery from tactile allodynia was also produced by direct suppression of dividing astrocytes by intrathecal administration of the cell cycle inhibitor flavopiridol to nerve-injured rats. Together, these results imply that the Janus kinase-signal transducers and activators of transcription 3 signalling pathway are critical transducers of astrocyte proliferation and maintenance of tactile allodynia and may be a therapeutic target for neuropathic pain.

Dataset Information

Zinc regulates the acute phase response and serum amyloid A production in response to sepsis through JAK-STAT3 signaling.

Publications

Zinc regulates the acute phase response and serum amyloid A production in response to sepsis through JAK-STAT3 signaling.

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