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Increased Serum Levels of LIGHT/TNFSF14 in Nonalcoholic Fatty Liver Disease: Possible Role in Hepatic Inflammation.

Otterdal K, Haukeland JW, Yndestad A, Dahl TB, Holm S, Segers FM, Gladhaug IP, Konopski Z, Damås JK, Halvorsen B, Aukrust P - Clin Transl Gastroenterol (2015)

Bottom Line: The tumor necrosis factor superfamily member 14, LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes), has been involved in various autoimmune disorders and has been shown to influence hepatic lipid metabolism.The mRNA expression of LIGHT in the liver tissue and mRNA levels of LIGHT and IL-8 in Huh7 hepatocytes were assessed by real-time quantitative reverse transcription-PCR. (i) Serum levels of LIGHT were significantly elevated in NAFLD patients (n=66) as compared with healthy controls (n=16), with no differences between simple steatosis (n=34) and nonalcoholic steatohepatitis (NASH) (n=32). (ii) Within the liver, NAFLD patients (n=14) had significantly increased mRNA levels of the two LIGHT receptors, herpes virus entry mediator and lymphotoxin β receptor (LTβR), as compared with controls (n=7), with no difference between simple steatosis (n=8) and NASH (n=6). (iii) LIGHT markedly increased the release of IL-8 in Huh7 hepatocytes in a time- and dose-dependent manner. (iv) The reactive oxygen species (ROS) H2O2 (hydrogen peroxide) enhanced the LIGHT-mediated release of IL-8 in Huh7 hepatocytes.We show increased levels of LIGHT and its two membrane-bound receptors in NAFLD, potentially promoting hepatic inflammation through ROS interaction.

View Article: PubMed Central - PubMed

Affiliation: 1] Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway [2] Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

ABSTRACT

Objectives: The tumor necrosis factor superfamily member 14, LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes), has been involved in various autoimmune disorders and has been shown to influence hepatic lipid metabolism. We hypothesized that LIGHT could also have a pathogenic role in nonalcoholic fatty liver disease (NAFLD).

Methods: Serum levels of LIGHT in NAFLD patients and control subjects, as well as LIGHT and interleukin (IL)-8 released from Huh7 (human hepatoma cell line) hepatocytes, were determined by enzyme-linked immunosorbent assay. The mRNA expression of LIGHT in the liver tissue and mRNA levels of LIGHT and IL-8 in Huh7 hepatocytes were assessed by real-time quantitative reverse transcription-PCR.

Results: (i) Serum levels of LIGHT were significantly elevated in NAFLD patients (n=66) as compared with healthy controls (n=16), with no differences between simple steatosis (n=34) and nonalcoholic steatohepatitis (NASH) (n=32). (ii) Within the liver, NAFLD patients (n=14) had significantly increased mRNA levels of the two LIGHT receptors, herpes virus entry mediator and lymphotoxin β receptor (LTβR), as compared with controls (n=7), with no difference between simple steatosis (n=8) and NASH (n=6). (iii) LIGHT markedly increased the release of IL-8 in Huh7 hepatocytes in a time- and dose-dependent manner. (iv) The reactive oxygen species (ROS) H2O2 (hydrogen peroxide) enhanced the LIGHT-mediated release of IL-8 in Huh7 hepatocytes.

Conclusion: We show increased levels of LIGHT and its two membrane-bound receptors in NAFLD, potentially promoting hepatic inflammation through ROS interaction. Our findings should encourage further studies on the role of LIGHT in NAFLD development and progression.

No MeSH data available.


Related in: MedlinePlus

Impact of LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) on the expression of interleukin-8 (IL-8) in Huh7 (human hepatoma cell line) hepatocytes in the presence of H2O2. Huh7 hepatocytes were stimulated with recombinant human LIGHT (300 ng/ml) with or without coincubation with two different concentrations of H2O2. The panels show mRNA levels in cell lysates (a), as assessed by real-time reverse transcription-PCR (RT-PCR), in relation to the control gene β-actin, and (b) protein levels in cell supernatants, as assessed by enzyme immunoassay, of IL-8 after 5 and 18 h stimulation, respectively. Data are given as mean±s.e.m., n=8. *P<0.05, **P<0.01, and ****P<0.0001 vs. US (unstimulated). †P<0.05, ††P<0.01, and †††P<0.001 vs. LIGHT when given alone.
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fig4: Impact of LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) on the expression of interleukin-8 (IL-8) in Huh7 (human hepatoma cell line) hepatocytes in the presence of H2O2. Huh7 hepatocytes were stimulated with recombinant human LIGHT (300 ng/ml) with or without coincubation with two different concentrations of H2O2. The panels show mRNA levels in cell lysates (a), as assessed by real-time reverse transcription-PCR (RT-PCR), in relation to the control gene β-actin, and (b) protein levels in cell supernatants, as assessed by enzyme immunoassay, of IL-8 after 5 and 18 h stimulation, respectively. Data are given as mean±s.e.m., n=8. *P<0.05, **P<0.01, and ****P<0.0001 vs. US (unstimulated). †P<0.05, ††P<0.01, and †††P<0.001 vs. LIGHT when given alone.

Mentions: Increased oxidative stress has been implicated in the pathogenesis of NAFLD.4 As shown in Figure 4, H2O2 increased the release of IL-8 from Huh7 cells, and notably, it also enhanced the stimulating effect of LIGHT on IL-8 release in these cells. Similar effects or even stronger effects were seen at the mRNA levels (Figure 4). LIGHT interact with HVEM and LTβR, and while HVEM in general showed very low expression in these cells, LTβR was clearly present and H2O2 enhanced the expression of LTβR, in particular when combined with LIGHT stimulation (Figure 5).


Increased Serum Levels of LIGHT/TNFSF14 in Nonalcoholic Fatty Liver Disease: Possible Role in Hepatic Inflammation.

Otterdal K, Haukeland JW, Yndestad A, Dahl TB, Holm S, Segers FM, Gladhaug IP, Konopski Z, Damås JK, Halvorsen B, Aukrust P - Clin Transl Gastroenterol (2015)

Impact of LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) on the expression of interleukin-8 (IL-8) in Huh7 (human hepatoma cell line) hepatocytes in the presence of H2O2. Huh7 hepatocytes were stimulated with recombinant human LIGHT (300 ng/ml) with or without coincubation with two different concentrations of H2O2. The panels show mRNA levels in cell lysates (a), as assessed by real-time reverse transcription-PCR (RT-PCR), in relation to the control gene β-actin, and (b) protein levels in cell supernatants, as assessed by enzyme immunoassay, of IL-8 after 5 and 18 h stimulation, respectively. Data are given as mean±s.e.m., n=8. *P<0.05, **P<0.01, and ****P<0.0001 vs. US (unstimulated). †P<0.05, ††P<0.01, and †††P<0.001 vs. LIGHT when given alone.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4816254&req=5

fig4: Impact of LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) on the expression of interleukin-8 (IL-8) in Huh7 (human hepatoma cell line) hepatocytes in the presence of H2O2. Huh7 hepatocytes were stimulated with recombinant human LIGHT (300 ng/ml) with or without coincubation with two different concentrations of H2O2. The panels show mRNA levels in cell lysates (a), as assessed by real-time reverse transcription-PCR (RT-PCR), in relation to the control gene β-actin, and (b) protein levels in cell supernatants, as assessed by enzyme immunoassay, of IL-8 after 5 and 18 h stimulation, respectively. Data are given as mean±s.e.m., n=8. *P<0.05, **P<0.01, and ****P<0.0001 vs. US (unstimulated). †P<0.05, ††P<0.01, and †††P<0.001 vs. LIGHT when given alone.
Mentions: Increased oxidative stress has been implicated in the pathogenesis of NAFLD.4 As shown in Figure 4, H2O2 increased the release of IL-8 from Huh7 cells, and notably, it also enhanced the stimulating effect of LIGHT on IL-8 release in these cells. Similar effects or even stronger effects were seen at the mRNA levels (Figure 4). LIGHT interact with HVEM and LTβR, and while HVEM in general showed very low expression in these cells, LTβR was clearly present and H2O2 enhanced the expression of LTβR, in particular when combined with LIGHT stimulation (Figure 5).

Bottom Line: The tumor necrosis factor superfamily member 14, LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes), has been involved in various autoimmune disorders and has been shown to influence hepatic lipid metabolism.The mRNA expression of LIGHT in the liver tissue and mRNA levels of LIGHT and IL-8 in Huh7 hepatocytes were assessed by real-time quantitative reverse transcription-PCR. (i) Serum levels of LIGHT were significantly elevated in NAFLD patients (n=66) as compared with healthy controls (n=16), with no differences between simple steatosis (n=34) and nonalcoholic steatohepatitis (NASH) (n=32). (ii) Within the liver, NAFLD patients (n=14) had significantly increased mRNA levels of the two LIGHT receptors, herpes virus entry mediator and lymphotoxin β receptor (LTβR), as compared with controls (n=7), with no difference between simple steatosis (n=8) and NASH (n=6). (iii) LIGHT markedly increased the release of IL-8 in Huh7 hepatocytes in a time- and dose-dependent manner. (iv) The reactive oxygen species (ROS) H2O2 (hydrogen peroxide) enhanced the LIGHT-mediated release of IL-8 in Huh7 hepatocytes.We show increased levels of LIGHT and its two membrane-bound receptors in NAFLD, potentially promoting hepatic inflammation through ROS interaction.

View Article: PubMed Central - PubMed

Affiliation: 1] Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway [2] Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

ABSTRACT

Objectives: The tumor necrosis factor superfamily member 14, LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes), has been involved in various autoimmune disorders and has been shown to influence hepatic lipid metabolism. We hypothesized that LIGHT could also have a pathogenic role in nonalcoholic fatty liver disease (NAFLD).

Methods: Serum levels of LIGHT in NAFLD patients and control subjects, as well as LIGHT and interleukin (IL)-8 released from Huh7 (human hepatoma cell line) hepatocytes, were determined by enzyme-linked immunosorbent assay. The mRNA expression of LIGHT in the liver tissue and mRNA levels of LIGHT and IL-8 in Huh7 hepatocytes were assessed by real-time quantitative reverse transcription-PCR.

Results: (i) Serum levels of LIGHT were significantly elevated in NAFLD patients (n=66) as compared with healthy controls (n=16), with no differences between simple steatosis (n=34) and nonalcoholic steatohepatitis (NASH) (n=32). (ii) Within the liver, NAFLD patients (n=14) had significantly increased mRNA levels of the two LIGHT receptors, herpes virus entry mediator and lymphotoxin β receptor (LTβR), as compared with controls (n=7), with no difference between simple steatosis (n=8) and NASH (n=6). (iii) LIGHT markedly increased the release of IL-8 in Huh7 hepatocytes in a time- and dose-dependent manner. (iv) The reactive oxygen species (ROS) H2O2 (hydrogen peroxide) enhanced the LIGHT-mediated release of IL-8 in Huh7 hepatocytes.

Conclusion: We show increased levels of LIGHT and its two membrane-bound receptors in NAFLD, potentially promoting hepatic inflammation through ROS interaction. Our findings should encourage further studies on the role of LIGHT in NAFLD development and progression.

No MeSH data available.


Related in: MedlinePlus