Cytokines in the liver

Ramadori, Giuliano; Armbrust, Thomas

doi:10.1097/00042737-200107000-00004

Cited by 219 publications

(159 citation statements)

References 64 publications

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“…This may mimic events in vivo in which an inflammatory hepatic cytokine microenvironment, found in hepatitis or cancer, dominated by IL‐1, IL‐2, IL‐6, IL‐12, IL‐15, IL‐18, IFNα, IFNγ, and TNFα/β 38, 39, may lead to the expansion of CD49a+ NK cells. Of the three patients in our cohort with significant enrichment of hepatic CD49a+ NK cells, one had hepatocellular carcinoma, one had aggressive colorectal cancer with synchronous lesions and bi‐lobar liver metastases and the third had colorectal metastases extending to the resection margins, suggesting that high frequencies of CD49a+ NK cells are associated with more severe liver disease.…”

Section: Discussionmentioning

confidence: 98%

IL‐12 and IL‐15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

Hydes

Noll

Salinas-Riester³

et al. 2017

Immunity Inflam & Disease

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IntroductionMurine hepatic NK cells exhibit adaptive features, with liver‐specific adhesion molecules CXCR6 and CD49a acting as surface markers.MethodsWe investigated human liver‐resident CXCR6+ and CD49a+ NK cells using RNA sequencing, flow cytometry, and functional analysis. We further assessed the role of cytokines in generating NK cells with these phenotypes from the peripheral blood.ResultsHepatic CD49a+ NK cells could be induced using cytokines and produce high quantities of IFNγ and TNFα, in contrast to hepatic CXCR6+ NK cells. RNA sequencing of liver‐resident CXCR6+ NK cells confirmed a tolerant immature phenotype with reduced expression of markers associated with maturity and cytotoxicity. Liver‐resident double‐positive CXCR6 + CD49a+ hepatic NK cells are immature but maintain high expression of Th1 cytokines as observed for single‐positive CD49a+ NK cells. We show that stimulation with activating cytokines can readily induce upregulation of both CD49a and CXCR6 on NK cells in the peripheral blood. In particular, IL‐12 and IL‐15 can generate CXCR6 + CD49a+ NK cells in vitro from NK cells isolated from the peripheral blood, with comparable phenotypic and functional features to liver‐resident CD49a+ NK cells, including enhanced IFNγ and NKG2C expression.ConclusionIL‐12 and IL‐15 may be key for generating NK cells with a tissue‐homing phenotype and strong Th1 cytokine profile in the blood, and links peripheral activation of NK cells with tissue‐homing. These findings may have important therapeutic implications for immunotherapy of chronic liver disease.

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Section: Discussionmentioning

confidence: 98%

IL‐12 and IL‐15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

Hydes

Noll

Salinas-Riester³

et al. 2017

Immunity Inflam & Disease

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“…To the best of our knowledge, most of the studies concerning EPO synthesis and regulation have been focused on hypoxic experimental conditions and within the kidney compartment. Although the central role of the liver in the regulation of acute-phase mediators and in the reorganization of the iron storage after injury has been deeply investigated, 31,32 however the EPO synthesis and production during acute-phase reaction and its regulatory mechanisms are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Cellular and molecular mechanisms regulating the hepatic erythropoietin expression during acute-phase response: a role for IL-6

Ramadori

Ahmad

Ramadori

2010

Laboratory Investigation

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The source of circulating erythropoietin (EPO), the mediators and the mechanisms involved in the upregulation of EPO gene expression during acute-phase reaction are still poorly understood. Acute-phase reaction was induced by either intramuscular turpentine oil (TO) or intraperitoneal lipopolysaccharide (LPS) administration into wild-type and interleukin (IL)-6 knockout (KO) mice. Animals were killed at different time points and blood, liver and muscle tissue were collected. Serum levels of EPO were measured by enzyme-linked immunoadsorbent assay; liver and injured muscle samples were processed for RNA isolation and for protein analysis. EPO, hypoxia-inducible factors 1a and 2a (HIF-1a and HIF-2a) mRNA were analyzed by RT-PCR and the protein levels were analyzed by western blot and electrophoretic mobility shift assay. HIF-1a and HIF-2a localization was performed through immunofluorescence staining. EPO, HIF-1 and HIF-2 gene and protein expression levels were also analyzed in isolated mouse hepatocytes after stimulation with IL-6. In the wild-type animals, EPO serum levels increased dramatically at 12 h after the insults together with the hepatic gene expression. In TO-treated animals, the EPO gene expression reached an 8.2-fold increase at 12 h, and in LPS-treated mice a similar induction was recorded at 6 h (about 4.5-fold increase). In the IL-6KO strain, the upregulation after the inflammatory stimuli was much lower (only 2.0-fold increase). A progressive upregulation of HIF-1a and HIF-2a was detectable until 6 h after the insults, but only HIF-1a upregulation was reduced in IL-6KO mice. In isolated hepatocytes, stimulation with a single dose of IL-6 induced a nuclear accumulation of HIF-1a, in parallel with an increase of EPO mRNA. No effect on HIF-2a expression was found. IL-6 appears to be the main regulator of EPO gene expression and a major contributor for HIF-1a induction in hepatocytes and Kupffer cells during acute-phase response. The increase of HIF-2a, predominantly expressed in endothelial cells and fibroblast-like cells, seems not to be affected by the lack of IL-6.

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“…However, sub-chronic PPARα-mediated immunosuppression likely effects the Kupffer cell defense mechanisms and cytokine production. Cytokines in the liver, which are mainly produced by Kupffer cells serve as important mediators of innate immune response, but also prime cells to proliferate or undergo apoptosis (Ramadori and Armbrust, 2001). There are conflicting reports with regards to the effects of peroxisome proliferators on cytokine production, and their importance to hepatocarcinogenesis.…”

Section: Gene Expression Profiling Reveals Pparα-mediated Immunosupprmentioning

confidence: 99%

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

Woods

Kosyk

Bradford

et al. 2007

Toxicology and Applied Pharmacology

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Administration of peroxisome proliferators to rodents causes proliferation of peroxisomes, induction of β-oxidation enzymes, hepatocelluar hypertrophy and hyperplasia, with chronic exposure ultimately leading to hepatocellular carcinomas. Many responses associated with peroxisome proliferators are nuclear receptor-mediated events involving peroxisome proliferators-activated receptor alpha (PPARα). A role for nuclear receptor-independent events has also been shown, with evidence of Kupffer cell-mediated free radical production, presumably through NAPDH oxidase, induction of redox-sensitive transcription factors involved in cytokine production and cytokinemediated cell replication following acute treatment with peroxisome proliferators in rodents. Recent studies have demonstrated, by using p47 phox -null mice which are deficient in NADPH oxidase, that this enzyme is not related to the phenotypic events caused by prolonged administration of peroxisome proliferators. In an effort to determine the timing of the transition from Kupffer cell-to PPARα-dependent modulation of peroxisome proliferator effects, gene expression was assessed in liver from Pparα-null, p47 phox -null and corresponding wild-type mice following treatment with 4-chloro-6-(2,3-xylidino)-pyrimidynylthioacetic acid (WY-14,643) for 8 h, 24 h, 72 h, 1 wk, or 4 wks. WY-14,643-induced gene expression in p47 phox -null mouse liver differed substantially from wildtype mice at acute doses and striking differences in baseline expression of immune related genes were evident. Pathway mapping of genes that respond to WY-14,643 in a time-and dose-dependent manner demonstrates suppression of immune response, cell death and signal transduction and promotion of lipid metabolism, cell cycle and DNA repair. Furthermore, these pathways were largely dependent on PPARα, not NADPH oxidase demonstrating a temporal shift in response to peroxisome proliferators. Overall, this study shows that NADPH oxidase-dependent events, while detectable following acute treatment, are transient and short-lived. To the contrary, a strong PPARα-specific gene signature was evident in mice that were continually exposed to WY-14,643.

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Cytokines in the liver

Cited by 219 publications

References 64 publications

IL‐12 and IL‐15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

IL‐12 and IL‐15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

Cellular and molecular mechanisms regulating the hepatic erythropoietin expression during acute-phase response: a role for IL-6

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

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