Down‐regulation of Fibrinogen Biosynthesis by Il‐4, Il‐10 and Il‐13

Vasse, Marc; Paysant, Jérôme; Soria, Jeannette; Mirshahi, S.; Vannier, Jean‐Pierre; Soria, Claudine

doi:10.1046/j.1365-2141.1996.d01-1731.x

Cited by 58 publications

(38 citation statements)

References 17 publications

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“…Moreover, IL-4 has been shown to inhibit lipogenesis stimulated by TNF-␣, IL-1, and IL-6 in mouse hepatocytes (36) and fibrinogen biosynthesis in the human HCC cell line HepG2 (37). In primary human hepatocytes, IL-4 could also induce the expression of cytochrome P-450 and GST␣ (38,39).…”

Section: Discussionmentioning

confidence: 99%

IL-4 Suppresses the Expression and the Replication of Hepatitis B Virus in the Hepatocellular Carcinoma Cell Line Hep3B

Lin

Shu

Chang

et al. 2003

The Journal of Immunology

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IL-4 has been known as a Th2 cytokine and can act on B cells, T cells, and monocytes. In this study we demonstrate that IL-4Rs are expressed on human hepatocellular carcinoma (HCC) cells. We found that IL-4 suppresses hepatitis B surface Ag (HBsAg) mRNA and HBsAg production in the Hep3B cell line, which contains an integrated hepatitis B virus (HBV) genome and constitutively secretes HBsAg. When Hep3B cells are further transfected with the plasmid pHBV3.6 that contains >1 U of HBV genome, IL-4 could suppress the production of all HBV RNA and secreted HBsAg and hepatitis B virus e Ag. Furthermore, an endogenous DNA polymerase activity assay shows a decrease in HBV DNA after IL-4 treatment. Using luciferase reporter assays we have demonstrated that IL-4 could suppress the activity of the surface promoter II and the core promotor (CP). To delineate how IL-4 suppressed the transcription of HBV genes, we have examined the effect of IL-4 on the expression of transcription factors that are known to bind to the core upstream regulatory sequence, which colocalizes with enhancer II of the HBV genome. Our results demonstrate that IL-4 suppresses the expression of C/EBPα. Furthermore, overexpression of C/EBPα blocked 43 and 30% of the IL-4-mediated suppression of CP activity and IL-4-induced suppression of pregenomic RNA, respectively. Finally, we have demonstrated that mutations affecting the C/EBPα-binding sites on core upstream regulatory sequence/enhancer II completely abolish the IL-4-mediated suppression of CP activity. Thus, down-regulation of C/EBPα may be involved in the anti-HBV effect of IL-4 in Hep3B cells.

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Section: Discussionmentioning

confidence: 99%

IL-4 Suppresses the Expression and the Replication of Hepatitis B Virus in the Hepatocellular Carcinoma Cell Line Hep3B

Lin

Shu

Chang

et al. 2003

The Journal of Immunology

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“…In case of an acute phase event in vivo, however, several other inflammatory mediators are also expressed, and IL6 interacts with several of these factors. Concerning the acute phase response of fibrinogen, interactions between IL6 and IL1␤, IL4, IL10, and IL13 have been described, underlining the complexity of the inflammatory response of fibrinogen in vivo (44,45). Therefore, our model system might have been too simplified relative to the real life situation.…”

Section: Discussionmentioning

confidence: 99%

A Hepatocyte Nuclear Factor-3 Site in the Fibrinogen β Promoter Is Important for Interleukin 6-induced Expression, and Its Activity Is Influenced by the Adjacent –148C/T Polymorphism

Verschuur

Jong

Felida³

et al. 2005

Journal of Biological Chemistry

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An elevated plasma fibrinogen level is an independent risk factor for cardiovascular disease. Therefore, an understanding of the regulation of fibrinogen expression is important. Inflammation and genetic variation of the fibrinogen ␤ gene regulate plasma fibrinogen levels, and there are indications that inflammation and genetic variation interact. The aim of our study was to gain more understanding of the regulation of the inflammatory response of the fibrinogen ␤ gene and to determine the effects of genetic variation. Luciferase reporter gene assays in hepatoma cells, mutation analysis, and electrophoretic mobility shift assays were used to investigate the transcriptional regulation of the fibrinogen ␤ promoter. We identified a hepatocyte nuclear factor-3 (HNF-3) site located just upstream of previously identified interleukin-6 (IL6)-responsive sequences. This HNF-3 site is essential for a full response of the promoter to IL6, which is a new function for HNF-3. The activity of the CCAAT box/enhancer-binding protein site (located 18 nucleotides downstream of the HNF-3 site and important to the IL6 response) depends on the integrity of the HNF-3 site and vice versa, explaining the necessity of HNF-3 in the IL6 response of the fibrinogen ␤ promoter. Furthermore, small interfering RNA to HNF-3 reduces the fibrinogen ␤ mRNA levels. The rare T allele of the ؊148C/T polymorphism, which is present between the binding sites of HNF-3 and CCAAT box/ enhancer-binding protein, interferes with this mechanism, and this polymorphism is in our assay system the only genetic determinant of IL6-induced promoter activity among six polymorphisms in the fibrinogen ␤ promoter.Inflammation is an important process in the development of cardiovascular disease, and increased plasma levels of inflammatory factors such as fibrinogen are consistently associated with an increased risk of cardiovascular disease (1-4). Inflammatory factors may play a dual role. On the one hand their plasma levels reflect the severity of inflammatory processes in the vessel wall, and on the other hand they can contribute directly to the development of the disease. Fibrinogen is present in the atherosclerotic plaque where it can contribute to the progression of atherosclerosis, for example by increasing the chemotaxis of smooth muscle cells and affecting the stability and structure of the plaque (5-8). Because of the relationship of fibrinogen with atherosclerosis, much attention has been paid to the regulation of fibrinogen levels under both basal and inflammatory conditions.The mature fibrinogen molecule is composed of three pairs of polypeptide chains: two ␣ chains, two ␤ chains, and two ␥ chains; and in vitro functional studies showed that synthesis of the ␤ chain is rate-limiting (9). Fibrinogen is expressed by the liver. Fibrinogen levels can strongly increase in response to intense acute phase stimuli such as trauma, surgery, or strenuous exercise, and fibrinogen levels are chronically elevated in the presence of mild (inflammatory) stimuli such as smoking...

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“…[12][13][14][15] Moreover, cytokines that mediate interferon-␥ elaboration, including interleukin (IL)-12 16 and IL-18, Conversely, IL-4 down-regulates inflammatory cytokine production and fibrinogen secretion in cultured vascular cells. 35 Therefore, the overall effect of IL-4 on atherosclerosis is difficult to predict from these in vitro studies.…”

Section: ؊1mentioning

confidence: 99%

Interleukin-4 Does Not Influence Development of Hypercholesterolemia or Angiotensin II-Induced Atherosclerotic Lesions in Mice

King

Cassis

Daugherty

2007

The American Journal of Pathology

111

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Interleukin-4 (IL-4) has been detected in both human and mouse atherosclerotic lesions, although its effects on the development of the disease are undefined. We determined the role of IL-4 in the most commonly used murine models of atherosclerosis by defining the effects of exogenous delivery and genetic deficiency of this cytokine on both hypercholesterolemia and AngII-induced atherosclerosis in apolipoprotein E (apoE) ؊/؊ mice and different dietary stimuli in low-density lipoprotein (LDL) receptor ؊/؊ mice. Exogenous administration of IL-4 (1.1 ng g ؊1 day ؊1 i.p. for 30 days) into female apoE ؊/؊ mice had no effect on lesion size or composition in mice fed normal or saturated fat diets. Also, IL-4 deficiency had no significant effect on the size or composition of atherosclerotic lesions in two vascular areas of male and female apoE ؊/؊ mice fed either a normal or saturated fat diet. IL-4 deficiency was also studied in age-matched male mice infused with AngII (1000 ng kg

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Down‐regulation of Fibrinogen Biosynthesis by Il‐4, Il‐10 and Il‐13

Cited by 58 publications

References 17 publications

IL-4 Suppresses the Expression and the Replication of Hepatitis B Virus in the Hepatocellular Carcinoma Cell Line Hep3B

IL-4 Suppresses the Expression and the Replication of Hepatitis B Virus in the Hepatocellular Carcinoma Cell Line Hep3B

A Hepatocyte Nuclear Factor-3 Site in the Fibrinogen β Promoter Is Important for Interleukin 6-induced Expression, and Its Activity Is Influenced by the Adjacent –148C/T Polymorphism

Interleukin-4 Does Not Influence Development of Hypercholesterolemia or Angiotensin II-Induced Atherosclerotic Lesions in Mice

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