Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type I collagen synthesis and deposition is generally indicative of irreversible damage in alcohol-induced cirrhosis in humans. However, in rodents, ethanol alone does not readily cause hepatic fibrosis. To determine whether this is because of a lack of ethanol-responsive elements, an artificial enhancer construct controlling rat type I collagen gene transcription was prepared in transgenic mice. The gene construct, ColCAT3.6, was a chimeric sequence containing the marker chloramphenicol acetyltransferase (CAT) gene linked to 3.5 kb of the rat alpha 1(I) 5'-flanking DNA, and 115 base pairs (bp) of transcribed collagen gene. Groups of transgenic mice were given 4 g/kg ethanol orally, twice daily for 4 weeks. As a positive control for hepatic fibrosis, transgenic mice were given intraperitoneal injections of CCl4, twice weekly for 4 weeks. Livers were assayed for CAT activity. Endogenous mouse collagen alpha 1(I) messenger RNA (mRNA) and transgene CAT mRNA were measured by RNase protection assays. Collagen synthesis in livers from the transgenic mice treated with ethanol were increased over controls, but the levels were not significantly different. Endogenous collagen alpha 1(I) steady-state mRNA levels in ethanol-treated mice were not significantly different compared with saline-treated controls. However, the transgene mRNA levels in ethanol-treated animals increased approximately 21-fold compared with saline-treated controls, as measured by RNase protection assays. Furthermore, the transgene product as measured by CAT activity in ethanol-treated mice was significantly increased threefold over saline-treated controls. We conclude that the 5'-flanking region of the rat alpha 1(I) collagen gene does contain regulatory elements that are strongly responsive to ethanol administration.
 ...
PMID:A collagen enhancer-promoter construct in transgenic mice is markedly stimulated by ethanol administration. 859 57

Interleukin 6 (IL-6) is a pleiotropic cytokine that induces many biological activities, including some aspects of the immune reaction and inflammatory responses. In the liver, IL-6 regulates the synthesis of a broad spectrum of acute-phase proteins. IL-6 is also known to be a factor involved in the immunoregulatory perturbations in patients with chronic liver diseases (CLDs). Here, we report that IL-6 can be induced by hepatitis B virus (HBV)-X protein, as evidenced by high levels of serum IL-6 in patients with CLD with HBV infection, IL-6 productions observed in HBV-X-transfected cells, and transcriptional transactivations of the IL-6 gene by HBV-X. We determined serum levels of IL-6 in patients with chronic hepatitis B (CH-B), chronic hepatitis C (CH-C), liver cirrhosis (LC) caused by hepatitis B, and LC with hepatocellular carcinoma (HCC) caused by hepatitis B (LC+HCC). Mean serum levels of IL-6 in all CLD patients were higher than those in normal controls, and the difference was statistically significant (P < 0.05). Mean IL-6 levels of LC and LC+HCC patients were significantly higher than those of CH-B patients (P < 0.05). Because the etiological factor in all cases except CH-C (CH-B, LC, and LC+HCC) was HBV, we checked the possibility of HBV-transactivator-X activation of IL-6 promoter. Using deletion constructs of 5'-flanking regulatory regions of the IL-6 gene linked to the chloramphenicol acetyltransferase gene as a reporter, we found that the binding of nuclear factor-kappaB to a cis element is essential and sufficient for the induction of the IL-6 gene by HBV-X. We also found that HBV-X enhances the binding of two subunits of nuclear factor-kappaB (p65 and p52) to their target DNA binding sequences. These observations are relevant, in that HBV-X might play an important role in hepatic inflammation and diseases by up-regulating IL-6 production, which can eventually lead to LC and HCC.
 ...
PMID:Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells. 967 46

Hepatic stellate cells (HSCs) become activated into myofibroblast-like cells during the early stages of hepatic injury associated with fibrogenesis. The subsequent dysregulation of alphaI(I) collagen gene expression is a central pathogenetic step during the development of cirrhosis. Our recent study in rat HSCs (Davis, B. H., Chen, A., and Beno, D. (1996) J. Biol. Chem. 271, 11039-11042) found that ERK1,2 activation might be required for maximal alphaI(I) collagen gene expression. However, the role of the parallel JNK cascade in regulating alphaI(I) collagen gene expression was unknown. In this study, we initially found that UV irradiation of HSCs activated JNK but not ERK1,2. Furthermore, UV irradiation increased endogenous alpha I(I) collagen mRNA abundance and stimulated alpha I(I) collagen gene transcription in HSCs. The effect of the activation of JNK and Jun on alpha I(I) collagen gene expression was further evaluated via transfection of chloramphenicol acetyltransferase reporter plasmids with various sizes of truncated 5' upstream promoter sequence (UPS) of the alphaI(I) collagen gene. This revealed that dominant negative transcription factor JUN suppressed alpha I(I) collagen gene transcription in HSCs maintained in media with 20% serum and constitutively activated JUN increased alphaI(I) collagen gene transcription in HSCs cultured in media with 0.4% serum. UV activated JNK utilized a distal GC box in the 5'-UPS of the collagen gene to regulate gene transcription. This observation was confirmed by site-directed mutagenesis. In co-transfection experiments, the col-chloramphenicol acetyltransferase reporter with a mutagenized GC box was not suppressed by dn-JUN and was not stimulated by activated JUN or by UV irradiation. Southwestern blotting analyses and gel shift assays with basic transcription element-binding protein antiserum suggested that the GC box was bound by basic transcription element-binding protein, a recently described DNA-binding protein. In conclusion, the current study combined with our previous report suggests that ERK1,2 and JNK cascades regulate alphaI(I) collagen expression in HSCs through different regions of the 5'-UPS of the gene. The distal GC box in the 5'-UPS of the alphaI(I) collagen gene may play a central role in receiving extracellular signals through the JNK pathway.
 ...
PMID:UV irradiation activates JNK and increases alphaI(I) collagen gene expression in rat hepatic stellate cells. 986 24