Cooperative effects of hepatitis B virus and TNF may play important roles in the activation of metabolic pathways through the activation of NF-κB.
Elevated levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β are often observed in the sera of hepatitis B virus (HBV)-infected patients. It is well known that these cytokines activate nuclear factor-κB (NF-κB)-signaling, and are associated with endoplasmic reticulum (ER) stress. We investigated whether HBV or HBV X protein (HBx) enhanced the activation of NF-κB in the presence of TNF and/or IL-1β, and their effects on the expression of metabolic pathway‑associated genes. We examined whether HBV or HBx enhanced cytokine-induced activation of NF-κB in hepatocytes, using a reporter assay, in the presence or absence of TNF and/or IL-1β. The expression of insulin-like growth factor binding protein 1 (IGFBP1), one of the NF-κB target genes was also examined. The expression of metabolic pathway-associated genes in HepG2 and HepG2.2.15 cells in the presence or absence of TNF was evaluated by RT-qPCR. Human hepatocytes expressed TNF receptors and IL-1 receptors. NF-κB was activated by cooperation between HBx and TNF in human hepatocytes. We observed IGFBP1 expression in HBV infection and that a number of metabolic pathway-associated genes were upregulated in HepG2.2.15 cells, compared with HepG2 cells with or without TNF treatment. We observed the cooperative effects of HBV and TNF which enhanced the activation of NF-κB as well as upregulated the expression of metabolic pathway-associated genes in hepatocytes. These effects may be important in the development of HBV-associated metabolic syndrome.
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Shuang
S
Wu
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Tatsuo
T
Kanda
Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Shingo
S
Nakamoto
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Xia
X
Jiang
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Masato
M
Nakamura
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Reina
R
Sasaki
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Yuki
Y
Haga
Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Hiroshi
H
Shirasawa
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.
Osamu
O
Yokosuka
D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D006515:Hepatitis B virus / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D018970:Insulin-Like Growth Factor Binding Protein 1; D053583:Interleukin-1beta; D007976:Leupeptins; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde