Hepatocytes produce tumor necrosis factor‐α and interleukin‐6 in response to <i>Porphyromonas gingivalis</i>

Takano, M.; Sugano, Naoyuki; Mochizuki, Susumu; Koshi, Ryosuke; Narukawa, Tetsuya; Sawamoto, Y.; Ito, Katsuhiko

doi:10.1111/j.1600-0765.2011.01408.x

Cited by 9 publications

(9 citation statements)

References 42 publications

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“…Many proinflammatory cytokine receptors such as IL-6 receptor, TNF-α receptor, IL-1β receptor, and IFN-γ receptor are expressed in hepatocytes. Although several reports showed that hepatocytes can produce these inflammatory cytokines under certain conditions 35 , 36 , innate immune cells, especially Kupffer cells in the liver are believed to the main source of proinflammatory cytokines during acute infections 16 , 37 . We tried to verify whether similar things happen to DAMPs.…”

Section: Resultsmentioning

confidence: 99%

Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells

Tang

et al. 2018

Cell Death Dis

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The damage-associated molecular pattern molecules (DAMPs) released by necrotic cells can trigger inflammatory response, which will facilitate the clearance of these dead cells. Neutrophil mobilization is a very important step for the dead cell clearance, however the detailed mechanisms for DAMPs induce neutrophil mobilization remains largely elusive. In this study, by using a necrotic cell-induced neutrophil mobilization mice model, we found that both neutrophil number and percentage rapidly (as early as 30 min) increased with necrotic cells but not live cell treatment. CXCL1 was rapidly increased in the serum and was responsible for the neutrophil mobilization when treated with necrotic cells. We further demonstrated that the hepatocytes in the liver were the main source of CXCL1 production in response to necrotic cells challenge. However, the hepatocytes did not express CXCL1 when incubating with necrotic cells alone. When Kupffer cells were ablated, the increased CXCL1 levels as well as neutrophil mobilization were abolished with necrotic cells challenge. Moreover, we clarified Kupffer cells-derived TNF-α activates the NF-κB pathway in hepatocytes and promote hepatocytes to express CXCL1. In summary, we showed that the liver is the main source for necrotic cell-induced CXCL1 production and neutrophil mobilization. Kupffer cells in the liver sense DAMPs and release TNF-α to activate the NF-κB pathway in hepatocytes. The interaction between Kupffer cells and hepatocytes is critical for CXCL1 production.

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Section: Resultsmentioning

confidence: 99%

Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells

Tang

et al. 2018

Cell Death Dis

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“…However, there was no TNF‐α release from Hepa 1–6 cells, which is in agreement with the observation that under in vitro conditions hepatocytes (Hepa 1–6 cells) can only produce TNF‐α production during co‐culture with macrophages. [ 64 ]…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Differences in Cell Death Responses to Metal‐Based Engineered Nanomaterials in Kupffer Cells and Hepatocytes

Wang

Chang

Jiang

et al. 2020

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The mononuclear phagocyte system in the liver is a frequent target for nanoparticles (NPs). A toxicological profiling of metal‐based NPs is performed in Kupffer cell (KC) and hepatocyte cell lines. Sixteen NPs are provided by the Nanomaterial Health Implications Research Consortium of the National Institute of Environmental Health Sciences to study the toxicological effects in KUP5 (KC) and Hepa 1–6 cells. Five NPs (Ag, CuO, ZnO, SiO2, and V2O5) exhibit cytotoxicity in both cell types, while SiO2 and V2O5 induce IL‐1β production in KC. Ag, CuO, and ZnO induced caspase 3 generated apoptosis in both cell types is accompanied by ion shedding and generation of mitochondrial reactive oxygen species (ROS) in both cell types. However, the cell death response to SiO2 in KC differs by inducing pyroptosis as a result of potassium efflux, caspase 1 activation, NLRP3 inflammasome assembly, IL‐1β release, and cleavage of gasdermin‐D. This releases pore‐performing peptide fragments responsible for pyroptotic cell swelling. Interestingly, although V2O5 induces IL‐1β release and delays caspase 1 activation by vanadium ion interference in membrane Na+/K+ adenosine triphosphate (ATP)ase activity, the major cell death mechanism in KC (and Hepa 1–6) is caspase 3 mediated apoptosis. These findings improve the understanding of the mechanisms of metal‐based engineered nanomaterial (ENM) toxicity in liver cells toward comprehensive safety evaluation.

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“…However, more recent investigations have indicated that this is in fact not the case. Hepatocytes mount a robust response to challenge with either LPS or IL-1b to produce key inflammatory cytokines, including IL-6, TNFa, and IL-1b (Liu et al, 2002;Panesar et al, 1999;Spencer et al, 2013;Takano et al, 2012;Yoshigai et al, 2014). It is also now well known that hepatocytes express all the necessary machinery to respond to bacterial sepsis , TABLE 5 Expression level of IL-1b, IL-6, TNFa, and IL1-Ra in wild-type and PXR-KO PCHs PCHs isolated from wild-type (n = 6) or PXR-KO mice (n = 6) were pretreated for 24 hours with either vehicle (0.1% dimethylsulfoxide) or PCN (10 mM).…”

Section: Discussionmentioning

confidence: 99%

Pregnane X Receptor Modulates the Inflammatory Response in Primary Cultures of Hepatocytes

et al. 2014

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Bacterial sepsis is characterized by a rapid increase in the expression of inflammatory mediators to initiate the acute phase response in liver. Inflammatory mediator release is counterbalanced by the coordinated expression of anti-inflammatory molecules such as interleukin 1 receptor antagonist (IL1-Ra) through time. This study determined whether activation of pregnane X receptor (PXR, NR1I2) alters the lipopolysaccharide (LPS)-inducible gene expression program in primary cultures of hepatocytes (PCHs). Preactivation of PXR for 24 hours in PCHs isolated from wild-type mice suppressed the subsequent LPS-inducible expression of the key inflammatory mediators interleukin 1b (IL-1b), interleukin 6 (IL-6), and tumor necrosis factor a (TNFa) but not in PCHs isolated from Pxr-null (PXR-knockout [KO]) mice. Basal expression of key inflammatory cytokines was elevated in PCHs from PXR-KO mice. Stimulation of PCHs from PXR-KO mice with LPS alone produced enhanced levels of IL-1b when compared with wild-type mice. Experiments performed using PCHs from both humanized-PXR transgenic mice as well as human donors indicate that prolonged activation of PXR produces an increased secretion of IL1-Ra from cells through time. Our data reveal a working model that describes a pivotal role for PXR in both inhibiting as well as in resolving the inflammatory response in hepatocytes. Understanding the molecular details of how PXR is converted from a positive regulator of drug-metabolizing enzymes into a transcriptional suppressor of inflammation in liver will provide new pharmacologic strategies for modulating inflammatory-related diseases in the liver and intestine.Pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor (NR) superfamily member expressed at high levels within the enterohepatic system of mammals. The biologic function of PXR is mediated together with its obligate partner retinoid X receptor a Lehmann et al., 1998). To date, the ligands identified for PXR have been numerous, and they are structurally diverse as naturally occurring steroids , antibiotics (Lehmann et al., 1998), bile acids (Staudinger et al., 2001a;Xie et al., 2001;Goodwin et al., 2003), anticancer agents (Desai et al., 2002;Nallani et al., 2004), and the active ingredients in several herbal remedies (Moore et al., 2000;Brobst et al., 2004;Ding and Staudinger, 2005). Ligand-activated PXR positively regulates the drug-inducible expression of genes encoding key drug transporters and drug metabolizing enzymes that function coordinately to increase the uptake, metabolism, excretion, and efflux of xenobiotics from the body. In this way, PXR activation is associated with increased metabolism and clearance of a myriad of potentially toxic compounds, and is classically thought of as a protective response.Clinical treatment with PXR activators can also lead to the repression or attenuation of other biochemical pathways in liver and intestine including both energy metabolism and the inflammatory response (Moreau et al., 2008). For example, it wa...

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Hepatocytes produce tumor necrosis factor‐α and interleukin‐6 in response to Porphyromonas gingivalis

Abstract: The results obtained in the present study show that P. gingivalis extract induces TNF-α and IL-6 in an in vitro liver model and that macrophage-derived TNF-α mediates the induction of TNF-α in hepatocytes.

Cited by 9 publications

References 42 publications

Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells

Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells

Mechanistic Differences in Cell Death Responses to Metal‐Based Engineered Nanomaterials in Kupffer Cells and Hepatocytes

Pregnane X Receptor Modulates the Inflammatory Response in Primary Cultures of Hepatocytes

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