Interleukin‐1β induces tumor necrosis factor‐α secretion from rat hepatocytes

Yoshigai, Emi; Hara, Tsunekatsu; Inaba, Hiroyuki; Hashimoto, Iwao; Tanaka, Yoshito; Kaibori, Masaki; Kimura, Tetsuya; Okumura, Tadayoshi; Kwon, A‐Hon; Nishizawa, Mikio

doi:10.1111/hepr.12157

Cited by 43 publications

(51 citation statements)

References 42 publications

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“…Importantly, treatment of liver with LPS leads to release of proinflammatory cytokines IL1b and TNFa from both nonparenchymal cells and hepatocytes. Stimulation with IL-1b induces TNFa secretion from rat hepatocytes, and stimulation of hepatocytes with either IL-1b or TNFa produces IL-6 secretion (Panesar et al, 1999;Yoshigai et al, 2014). Hence, there are multiple levels of interconnection and amplification that occur rapidly between and among inflammatory cytokines after bacterial sepsis.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…However, many of the cytokines produced by hepatic immune cells can cause hepatocyte injury, and IL-1β, IL-6 andTNF-α are especially dangerous [2,3]. Furthermore, IL-1β has been reported to induce high levels of TNF-α [4,5] and IL-6 [6] in hepatocytes and osteoblasts, respectively. Because 80% of the liver volume consists of hepatocytes [7], the prevention of hepatocyte injury is an important consideration when designing therapeutic strategies [2].…”

Section: Introductionmentioning

confidence: 99%

Lipocalin 2 Upregulation Protects Hepatocytes from IL1-β-Induced Stress

Xue

Yang

et al. 2015

Cell Physiol Biochem

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Background: Lipocalin 2 (LCN2), a protein primarily produced by hepatocytes, is highly upregulated under various conditions that induce cellular stress, such as intoxication, infection or inflammation. However, the precise biological functions and underlying mechanisms of LCN2 in hepatocytes remains unknown. Methods: Hepatocyte stress was successfully induced by treating Huh7 cells with interleukin-1β (IL-1β). Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α) and LCN2 levels were measured in IL-1β treated Huh7 cells and supernatant. Additionally, microarray analysis was conducted to identify genes differentially expressed in LCN2-silenced and control Huh7 cells. Results: TNF-α, IL-6 and LCN2 were significantly elevated in Huh7 cells after IL-1β) treatment. In LCN2-silenced Huh7 cells, expression of IL-6 and TNF-α was significantly increased when compared with the expression levels of control Huh7 cells. Furthermore, differentially expressed genes were observed between the LCN2-silenced and control cells. Microarray analysis indicated that LCN2 acted by influencing genes involved in protein metabolism, stress response, cell cycle and proliferation. Conclusions: Our results suggest that LCN2 upregulation protects hepatocytes from IL-1β-induced stress. Additionally, our microarray analysis of LCN2-silenced and control cells provides a better understanding of the mechanisms that may be influenced by LCN2 induction.

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“…This method is referred to as natural antisense transcript-targeted regulation (NATRE) technology [22] . In contrast, when sense oligonucleotides corresponding to other mRNAs that are involved in inflammation (e.g., mRNAs encoding TNF-alpha, nuclear factor-kappaB p65 subunit, and several chemokines) were introduced into hepatocytes, their mRNA levels increased (discordant regulation) [23,24] .…”

Section: Inflammation and Infectionmentioning

confidence: 98%

“…Both sense oligodeoxyribonucleotides [11,[21][22][23][24] and antisense oligoribonucleotides (asRNA mimics) [6] have been successfully used to interfere with this interaction. The copy number of an asRNA is generally lower than that of an mRNA, although asRNAs have high specificity to their cognate mRNAs.…”

Section: Regulatory Rna Networkmentioning

confidence: 99%

RNA Networks that Regulate mRNA Expression and their Potential as Drug Targets

Nishizawa

Kimura

2015

RNA Dis

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Natural antisense transcripts (asRNAs) transcribed from eukaryotic genes are primarily long transcripts that do not code for proteins. Transcriptome analyses have revealed that asRNAs exhibit diverse functional roles in the regulation of gene expression. In the case of inducible genes, asRNAs epigenetically affect their expression or post-transcriptionally affect stability and translatability of their mRNAs. Many low-copy-number asRNAs regulate the expression levels of mRNAs through cis-controlling elements in the mRNA in concert with trans-acting factors, such as RNA-binding proteins and microRNAs. Recently, a competitive endogenous RNA (ceRNA) hypothesis was postulated as the basis of a functional network, comprising mRNAs, asRNAs, and microRNAs. This network finely tunes mRNA expression by common microRNA-responsive elements being present among mRNAs and asRNAs, permitting the redirection of microRNAs between the two. Examples of the ceRNA-mediated cross-regulation of mRNA expression are observed in the phosphatase and tensin homolog mRNA network and the interferon-alpha1 mRNA network. In such regulatory RNA networks, an mRNA, its corresponding asRNAs (high specificity), microRNAs (low specificity), and RNA-binding proteins mutually interact. Both asRNAs and microRNAs are involved in the pathogenesis or pathophysiology of various diseases, such as cancer, inflammation, and infection. Simple disruption of an asRNA or a microRNA can often show off-target effects due to complicated interactions inside and outside the regulatory RNA networks. Therefore, drugs that target asRNAs should be developed to minimize off-target effects and to target interactions that are dysregulated in disease.

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Interleukin‐1β induces tumor necrosis factor‐α secretion from rat hepatocytes

Cited by 43 publications

References 42 publications

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

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

Lipocalin 2 Upregulation Protects Hepatocytes from IL1-β-Induced Stress

RNA Networks that Regulate mRNA Expression and their Potential as Drug Targets

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