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Substitution in Amino Acid 70 of Hepatitis C Virus Core Protein Changes the Adipokine Profile via Toll-Like Receptor 2/4 Signaling.

Uraki S, Tameda M, Sugimoto K, Shiraki K, Takei Y, Nobori T, Ito M - PLoS ONE (2015)

Bottom Line: The effects of toll-like receptor (TLR)2/4 inhibition on IL-6 production by 3T3-L1 induced by HCV core protein were examined.IL-6 production was significantly increased and adiponectin production was reduced without a change in triglyceride content by treatment with 70Q compared to 70R core protein in both murine and human adipocytes.IL-6 induction of 3T3-L1 cells treated by 70Q HCV core protein was significantly inhibited with anti-TLR2 antibody by 42%, and by TLR4 inhibitor by 40%.

View Article: PubMed Central - PubMed

Affiliation: First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.

ABSTRACT

Background & aims: It has been suggested that amino acid (aa) substitution at position 70 from arginine (70R) to glutamine (70Q) in the genotype 1b hepatitis C virus (HCV) core protein is associated with insulin resistance and worse prognosis. However, the precise mechanism is still unclear. The aim of this study was to investigate the impact of the substitution at position 70 in HCV core protein on adipokine production by murine and human adipocytes.

Methods: The influence of treatment with HCV core protein (70R or 70Q) on adipokine production by both 3T3-L1 and human adipocytes were examined with real-time PCR and enzyme-linked immunosorbent assay (ELISA), and triglyceride content was also analyzed. The effects of toll-like receptor (TLR)2/4 inhibition on IL-6 production by 3T3-L1 induced by HCV core protein were examined.

Results: IL-6 production was significantly increased and adiponectin production was reduced without a change in triglyceride content by treatment with 70Q compared to 70R core protein in both murine and human adipocytes. IL-6 induction of 3T3-L1 cells treated by 70Q HCV core protein was significantly inhibited with anti-TLR2 antibody by 42%, and by TLR4 inhibitor by 40%.

Conclusions: Our study suggests that extracellular HCV core protein with substitution at position 70 enhanced IL-6 production and reduced adiponectin production from visceral adipose tissue, which can cause insulin resistance, hepatic steatosis, and ultimately development of HCC.

No MeSH data available.


Related in: MedlinePlus

The influence of TLR2/4 inhibition on IL-6 secretion induced by HCV core protein.(A) 3T3-L1 cells stimulated by a TLR2 agonist, Pam3CSK4, induced IL-6 secretion, and it was inhibited by 85% with anti-TLR2 antibody. IL-6 induction of 3T3-L1 cells treated by HCV core protein was significantly inhibited with anti-TLR2 antibody by 42% in the 70Q group (p<0.05) and 31% in the 70R group, though it did not reach statistical significance, probably due to small sample size. (B) LPS induced IL-6 secretion, and VIPER inhibited it by 56%. IL-6 induction of 3T3-L1 cells treated by 70Q was significantly inhibited by VIPER, and the ratio of inhibition was 40% (p<0.05); however, it did not change IL-6 production with 70R HCV core protein.
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pone.0131346.g006: The influence of TLR2/4 inhibition on IL-6 secretion induced by HCV core protein.(A) 3T3-L1 cells stimulated by a TLR2 agonist, Pam3CSK4, induced IL-6 secretion, and it was inhibited by 85% with anti-TLR2 antibody. IL-6 induction of 3T3-L1 cells treated by HCV core protein was significantly inhibited with anti-TLR2 antibody by 42% in the 70Q group (p<0.05) and 31% in the 70R group, though it did not reach statistical significance, probably due to small sample size. (B) LPS induced IL-6 secretion, and VIPER inhibited it by 56%. IL-6 induction of 3T3-L1 cells treated by 70Q was significantly inhibited by VIPER, and the ratio of inhibition was 40% (p<0.05); however, it did not change IL-6 production with 70R HCV core protein.

Mentions: 3T3-L1 cells stimulated by a TLR2 agonist, Pam3CSK4, had remarkably induced IL-6 secretion, and it was inhibited by 85% with anti-TLR2 antibody. IL-6 induction of 3T3-L1 cells treated by HCV core protein was significantly inhibited with anti-TLR2 antibody by 42% in the 70Q group (p<0.05) and by 31% in the 70R group, though it did not reach statistical significance, probably due to the small number of samples (Fig 6A). LPS also induced marked IL-6 secretion, and VIPER, an antagonist of TLR4, inhibited it by 56%. IL-6 induction of 3T3-L1 cells treated by 70Q was also significantly inhibited by VIPER, and the ratio of inhibition was 40% (p<0.05); however, it did not change IL-6 production with 70R HCV core protein (Fig 6B). These results suggested that 70Q might induce IL-6 secretion via both TLR2 and TLR4, although production of IL-6 via TLR4 was not significant in cells treated with 70R HCV core protein.


Substitution in Amino Acid 70 of Hepatitis C Virus Core Protein Changes the Adipokine Profile via Toll-Like Receptor 2/4 Signaling.

Uraki S, Tameda M, Sugimoto K, Shiraki K, Takei Y, Nobori T, Ito M - PLoS ONE (2015)

The influence of TLR2/4 inhibition on IL-6 secretion induced by HCV core protein.(A) 3T3-L1 cells stimulated by a TLR2 agonist, Pam3CSK4, induced IL-6 secretion, and it was inhibited by 85% with anti-TLR2 antibody. IL-6 induction of 3T3-L1 cells treated by HCV core protein was significantly inhibited with anti-TLR2 antibody by 42% in the 70Q group (p<0.05) and 31% in the 70R group, though it did not reach statistical significance, probably due to small sample size. (B) LPS induced IL-6 secretion, and VIPER inhibited it by 56%. IL-6 induction of 3T3-L1 cells treated by 70Q was significantly inhibited by VIPER, and the ratio of inhibition was 40% (p<0.05); however, it did not change IL-6 production with 70R HCV core protein.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487891&req=5

pone.0131346.g006: The influence of TLR2/4 inhibition on IL-6 secretion induced by HCV core protein.(A) 3T3-L1 cells stimulated by a TLR2 agonist, Pam3CSK4, induced IL-6 secretion, and it was inhibited by 85% with anti-TLR2 antibody. IL-6 induction of 3T3-L1 cells treated by HCV core protein was significantly inhibited with anti-TLR2 antibody by 42% in the 70Q group (p<0.05) and 31% in the 70R group, though it did not reach statistical significance, probably due to small sample size. (B) LPS induced IL-6 secretion, and VIPER inhibited it by 56%. IL-6 induction of 3T3-L1 cells treated by 70Q was significantly inhibited by VIPER, and the ratio of inhibition was 40% (p<0.05); however, it did not change IL-6 production with 70R HCV core protein.
Mentions: 3T3-L1 cells stimulated by a TLR2 agonist, Pam3CSK4, had remarkably induced IL-6 secretion, and it was inhibited by 85% with anti-TLR2 antibody. IL-6 induction of 3T3-L1 cells treated by HCV core protein was significantly inhibited with anti-TLR2 antibody by 42% in the 70Q group (p<0.05) and by 31% in the 70R group, though it did not reach statistical significance, probably due to the small number of samples (Fig 6A). LPS also induced marked IL-6 secretion, and VIPER, an antagonist of TLR4, inhibited it by 56%. IL-6 induction of 3T3-L1 cells treated by 70Q was also significantly inhibited by VIPER, and the ratio of inhibition was 40% (p<0.05); however, it did not change IL-6 production with 70R HCV core protein (Fig 6B). These results suggested that 70Q might induce IL-6 secretion via both TLR2 and TLR4, although production of IL-6 via TLR4 was not significant in cells treated with 70R HCV core protein.

Bottom Line: The effects of toll-like receptor (TLR)2/4 inhibition on IL-6 production by 3T3-L1 induced by HCV core protein were examined.IL-6 production was significantly increased and adiponectin production was reduced without a change in triglyceride content by treatment with 70Q compared to 70R core protein in both murine and human adipocytes.IL-6 induction of 3T3-L1 cells treated by 70Q HCV core protein was significantly inhibited with anti-TLR2 antibody by 42%, and by TLR4 inhibitor by 40%.

View Article: PubMed Central - PubMed

Affiliation: First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.

ABSTRACT

Background & aims: It has been suggested that amino acid (aa) substitution at position 70 from arginine (70R) to glutamine (70Q) in the genotype 1b hepatitis C virus (HCV) core protein is associated with insulin resistance and worse prognosis. However, the precise mechanism is still unclear. The aim of this study was to investigate the impact of the substitution at position 70 in HCV core protein on adipokine production by murine and human adipocytes.

Methods: The influence of treatment with HCV core protein (70R or 70Q) on adipokine production by both 3T3-L1 and human adipocytes were examined with real-time PCR and enzyme-linked immunosorbent assay (ELISA), and triglyceride content was also analyzed. The effects of toll-like receptor (TLR)2/4 inhibition on IL-6 production by 3T3-L1 induced by HCV core protein were examined.

Results: IL-6 production was significantly increased and adiponectin production was reduced without a change in triglyceride content by treatment with 70Q compared to 70R core protein in both murine and human adipocytes. IL-6 induction of 3T3-L1 cells treated by 70Q HCV core protein was significantly inhibited with anti-TLR2 antibody by 42%, and by TLR4 inhibitor by 40%.

Conclusions: Our study suggests that extracellular HCV core protein with substitution at position 70 enhanced IL-6 production and reduced adiponectin production from visceral adipose tissue, which can cause insulin resistance, hepatic steatosis, and ultimately development of HCC.

No MeSH data available.


Related in: MedlinePlus