Expression of cyclooxygenase 2 and cytosolic phospholipase A2 in the liver tissue of patients with chronic hepatitis and liver cirrhosis

Cheng, Jidong; Imanishi, Hiroyasu; Iijima, Hiroko; Shimomura, Soji; Yamamoto, Tetsuya; Amuro, Yoshiki; Kubota, Akira; Hada, Toshikazu

doi:10.1016/s1386-6346(01)00177-2

Cited by 50 publications

(38 citation statements)

References 27 publications

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“…In the current study, we identified a novel IL-8 downstream proinflammatory factor, COX-2, in the presence of HBV infection. Although adult hepatocytes do not express COX-2 under normal conditions, the level of COX-2 in hepatocytes increases during chronic inflammatory liver diseases (20,55). COX-2 is also overexpressed in liver cirrhosis and may contribute to HCC development.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Induces a Novel Inflammation Network Involving Three Inflammatory Factors, IL-29, IL-8, and Cyclooxygenase-2

Gong

et al. 2011

The Journal of Immunology

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Chronic inflammation induced by hepatitis B virus (HBV) is a major causative factor associated with the development of cirrhosis and hepatocellular carcinoma. In this study, we investigated the roles of three inflammatory factors, IL-8, IL-29 (or IFN-λ1), and cyclooxygenase-2 (COX-2), in HBV infection. We showed that the expression of IL-29, IL-8, and COX-2 genes was enhanced in HBV-infected patients or in HBV-expressing cells. In HBV-transfected human lymphocytes and hepatocytes, IL-29 activates the production of IL-8, which in turn enhances the expression of COX-2. In addition, COX-2 decreases the production of IL-8, which in turn attenuates the expression of IL-29. Thus, we proposed that HBV infection induces a novel inflammation cytokine network involving three inflammatory factors that regulate each other in the order IL-29/IL-8/COX-2, which involves positive regulation and negative feedback. In addition, we also demonstrated that COX-2 expression activated by IL-8 was mediated through CREB and C/EBP, which maintains the inflammatory environment associated with HBV infection. Finally, we showed that the ERK and the JNK signaling pathways were cooperatively involved in the regulation of COX-2. We also demonstrated that IL-29 inhibits HBV replication and that IL-8 attenuates the expression of IL-10R2 and the anti-HBV activity of IL-29, which favors the establishment of persistent viral infection. These new findings provide insights for our understanding of the mechanism by which inflammatory factors regulate each other in response to HBV infection.

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Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus Induces a Novel Inflammation Network Involving Three Inflammatory Factors, IL-29, IL-8, and Cyclooxygenase-2

Gong

et al. 2011

The Journal of Immunology

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“…COX-2 is associated with liver pathogenesis, including fibrosis and carcinogenesis, and COX-2 inhibitors have exhibited significant anti-proliferative effects in several human HCC cell lines. [20][21][22][23] Here we observed dose-dependent growth inhibition and cell cycle arrest by a selective COX-2 inhibitor, etodolac, on two HCC cell lines. Our findings suggest that a selective COX-2 inhibitor might be effective for the chemopre- vention and treatment of HCC.…”

Section: Discussionmentioning

confidence: 99%

Involvement of cell cycle regulatory proteins and MAP kinase signaling pathway in growth inhibition and cell cycle arrest by a selective cyclooxygenase 2 inhibitor, etodolac, in human hepatocellular carcinoma cell lines

et al. 2004

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yclooxygenase 2 (COX-2) is a highly inducible, rate-limiting enzyme involved in the production of prostaglandins (PGs), prostacyclins and thromboxanes. COX-2 is expressed in response to a variety of proinflammatory agents and cytokines.1, 2) Overexpression of COX-2 has been demonstrated in various tumors such as colon cancer, pancreatic cancer and hepatocellular carcinoma (HCC).3-5) Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently being assessed for use in the prevention and treatment of colorectal cancer, based on epidemiologic, preclinical and experimental evidence. 6, 7) Although several studies have shown the up-regulation of COX-2 in cirrhotic tissues adjacent to HCC and well-differentiated HCC, the precise role of COX-2 in hepato-carcinogenesis remains unclear. 5,8) A recent report of ours has also shown that NS-398, a selective COX-2 inhibitor, inhibited growth and induced cell cycle arrest in HCC cell lines. 9) However, the mechanism by which COX-2 inhibitors cause growth inhibition and cell cycle arrest in HCC cells is not known.There is increasing evidence that perturbation of cell cycle regulation is an important contributing factor to cancer, including HCC. 10,11) There are two key checkpoints in the cell cycle, the G1-S and G2-M checkpoints. Cyclins, cyclin-dependent kinases (CDKs) and cyclin/CDK complexes have been found to control the progression of cells through the G0-G1, S and G2-

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“…Significantly, increased expression of COX-2 has been documented in cirrhotic livers from patients with HCV or HBV infections [15] and in various cancers [4]. In cirrhotic livers, COX-2 expression has been shown to increase significantly with inflammation and the progression of liver fibrosis, suggesting a role for COX-2 as a mediator of the transition from inflammation to cancer [15,16]. Furthermore, a study demonstrated that HBx-induced COX-2 expression contributes to tumor cell invasion [17].…”

Section: Introductionmentioning

confidence: 99%

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

Lim

Kwon

Cho³

et al. 2009

J Mol Med

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Chronic inflammation can be a major risk factor for cancer development and may contribute to the high worldwide incidence of hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) is known to be an important mediator of inflammatory responses; however, its link to hepatitis B virus (HBV)-mediated inflammatory responses has not been established. Here, we demonstrate that the expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon but not in cells transfected by HBV genome lacking the HBx gene. Notably, COX-2 induction was correlated with HBx's ability to increase reactive oxygen species (ROS) levels. Consistently with this, antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction. Interestingly, a mitochondria localization-defective mutant of HBx (HBx Δ68-117 ) neither increased intracellular ROS levels nor induced COX-2 expression. HBx 68-117 , which encodes only amino acids 68-117 and is sufficient for mitochondria localization, increased ROS levels but did not induce COX-2 expression. Similarly, HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but also failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction. Indeed, inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calciumdependent tyrosine kinase suppressed HBV-mediated COX-2 induction. Thus, the data indicate that both mitochondrial ROS and cytoplasmic calcium signaling are necessary for the COX-2 induction. Our studies revealed a pathophysiological link between HBV infection and hepatic inflammation, and this chain of events might contribute to early steps in HBV-associated liver carcinogenesis.

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Expression of cyclooxygenase 2 and cytosolic phospholipase A2 in the liver tissue of patients with chronic hepatitis and liver cirrhosis

Cited by 50 publications

References 27 publications

Hepatitis B Virus Induces a Novel Inflammation Network Involving Three Inflammatory Factors, IL-29, IL-8, and Cyclooxygenase-2

Hepatitis B Virus Induces a Novel Inflammation Network Involving Three Inflammatory Factors, IL-29, IL-8, and Cyclooxygenase-2

Involvement of cell cycle regulatory proteins and MAP kinase signaling pathway in growth inhibition and cell cycle arrest by a selective cyclooxygenase 2 inhibitor, etodolac, in human hepatocellular carcinoma cell lines

HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression

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