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

Murine macrophages express high levels of nitric oxide synthase and produce large amounts of nitric oxide (NO) when stimulated with certain cytokines in the presence of a trace amount of lipopolysaccharide (LPS). The stimulatory cytokines include interleukin-1 (IL-1), interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and migration inhibitory factor. Activated macrophages are highly effective killers of intra- and extra-cellular pathogens. However, as excessive NO can lead to immunopathology (diabetes, graft-v.-host disease, EAE, liver cirrhosis, rheumatoid arthritis), NO production is necessarily under tight regulation. A number of cytokines, including IL-4, IL-10 and transforming growth factor-beta, can down regulate the induction of NO synthase in macrophages. In addition, macrophages exposed to LPS alone and then stimulated with a mix of IFN-gamma and LPS express significantly lower levels of NO synthase than cells stimulated without pre-exposure to LPS. Furthermore, NO can reduce the activity of NO synthase by feedback inhibition, and also inhibit the production of IFN-gamma by Th1 cells (thus turning off its own synthesis from upstream). The regulatory pathways involve tyrosine kinase and protein kinase C.
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PMID:The role of nitric oxide in parasitic diseases. 751 Jan

An imbalance between T helper cell (Th)1 and Th2-like cytokines has been described in several chronic infectious diseases. We therefore analyzed the intrahepatic messenger RNA (mRNA) expression of Th1-like (interleukin [IL]-2, interferon [IFN]-gamma) and Th2-like (IL-4, IL-10) cytokines in chronic hepatitis C patients (n = 17) and controls (n = 6) and correlated the results with liver histology and intrahepatic viral load. Intrahepatic cytokine mRNA and hepatitis C virus (HCV) RNA were quantitatively assessed by polymerase chain reaction (PCR) using a dot-blot hybridization technique. Liver biopsy specimens were histologically graded using the Scheuer Score. IFN-gamma and IL-2 mRNA expression were significantly upregulated in chronic HCV vs. controls (P < .002, P < .04, respectively). Both correlated significantly with histological fibrosis and portal tract inflammation. In contrast, the expression of IL-10 mRNA was decreased in cirrhosis and chronic HCV compared with controls (P < .02, P < .0001, respectively). IL-4 mRNA was detected inconsistently at low levels in all groups. Intrahepatic viral load did not correlate with either cytokine expression or tissue injury. In conclusion, the progressive liver injury seen in chronic HCV is associated with the upregulation of intrahepatic Th1-like cytokines and the downregulation of IL-10, a Th2-like cytokine. These results suggest a role for delayed-type hypersensitivity immune reactions in HCV related liver injury.
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PMID:Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines. 885 73

Patients with cirrhosis of the liver frequently demonstrate anergy in intracutaneous tests and fail to respond to vaccination, suggesting impaired delayed hypersensitivity and other T cell-dependent functions in vivo. T cell activation through the coordinated interaction of different cells of the immune system (B cell, antigen-presenting cells (APC)) is an important step in the induction of cellular and humoral immune responses. Impaired T cell-dependent functions in patients with liver cirrhosis may thus be explained by defective T cell activation. We prospectively investigated T cell activation pathways in 12 patients (nine males, three females) with alcoholic liver cirrhosis (seven Child Pugh stage A and B (CP A + B), five Child Pugh stage C (CP C)) and five healthy controls and compared the in vitro results of T cell activation with data obtained in vivo, e.g. intracutaneous tests and vaccination against hepatitis B surface antigen (HBs-Ag). Five out of eight patients who completed vaccination against hepatitis B virus infection were non-responders; one of the three responders had a non-protective anti-HBs titre. Moreover, three of five patients with alcoholic liver cirrhosis CP A + B, and two out of three with CP C were anergic in intracutaneous tests to a set of diverse antigens. All parameters of T cell activation were normal, including proliferation mediated by CD2, CD3-T cell receptor (TCR) complex, and CD28; acquisition of responsiveness to exogenous IL-2 and IL-4; activation of proteinkinase C (PKC) by phorbol ester and calcium influx by addition of ionomycin. The ability of monocytes to deliver costimulatory signals was preserved in patients with alcoholic cirrhosis. In addition, serum of patients with alcoholic liver disease did not inhibit T cell proliferation. We conclude that, although in patients with alcoholic liver cirrhosis T cell-dependent functions are impaired in vivo, T cell activation pathways are not responsible for the observed immune defect.
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PMID:Analysis of T cell activation pathways in patients with liver cirrhosis, impaired delayed hypersensitivity and other T cell-dependent functions. 909 23

Kupffer cells (KC) play a central role in the initiation and perpetuation of hepatic inflammation, which, if uncontrolled, can result in tissue damage, fibrosis, and cirrhosis. Interleukin-10 (IL-10) can inhibit a range of macrophage functions. We hypothesized that the transcription, synthesis, and release of IL-10 may influence the development of liver injury. Rat KC were activated in vitro with lipopolysaccharide (LPS), and expression of IL-10 mRNA compared with IL-13 and IL-1beta by reverse-transcription polymerase chain reaction (RT-PCR). The effects of pretreatment with recombinant IL-10 (rIL-10) on KC phagocytosis, production of superoxide (SO), and tumor necrosis factor (TNF-) were examined by fluorescent activated cell sorter (FACS), reduction of ferricytochrome C, and bioassay, respectively. Rats were administered intraperitoneal carbon tetrachloride (CCl4), and expression of IL-10 mRNA and protein in vivo compared with IL-13 and IL-1beta by RT-PCR and immunoblotting. Results were correlated with histological inflammatory changes. Finally, IL-10 gene-deleted (IL-10-/-) mice and wild-type (WT) controls were administered intraperitoneal CCl4 biweekly for up to 70 days, and the development of inflammation and fibrosis compared by scoring histological changes. IL-10 mRNA was up-regulated early, both in KC in vitro and in whole liver in vivo, concurrent with that of IL-1beta. IL-10 was able to inhibit KC production of both SO and TNF- in vitro, and this was achieved more effectively than IL-4 or IL-13; no such effects were seen on KC phagocytosis. After 70 days of treatment with CCl4, IL-10-/- mice showed significantly more severe fibrosis and exhibited higher hepatic TNF- levels than WT controls. These results suggest that IL-10 synthesized during the course of liver inflammation and fibrosis may modulate KC actions, and influence subsequent progression of fibrosis.
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PMID:Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis. 982 39

The chronic alcoholic patient is usually immunosuppressed, but the significance of this phenomenon in terms of bile duct injury is unclear. The immunoreactivity of the bile duct cells was examined in a series of 69 frozen liver biopsy specimens obtained from patients with alcoholic liver disease, comprising 29 cases of cirrhosis, 26 of alcoholic hepatitis, 10 cases of alcoholic fatty liver, and 4 specimens from normal livers. Liver diseases such as primary biliary cirrhosis and human hepatic allograft rejection, known to have an autoimmune basis, share the characteristic feature of damage to the bile duct epithelial cells. In both instances the damage seems to be immune mediated, but the nature of the antigens involved is not established. We used the avidin-biotin-peroxidase complex method to test in alcoholic liver disease for the expression of a battery of surface antigen markers that have been incriminated in tissue injury and are usually present in lymphoid cells but also expressed by epithelium. In this study we investigated the expression of the following molecules: HLA class I (ABC) and class II (HLA-DR, HLA-DP, HLA-DQ), CD29, CD45RA, CD45RO, CD56, interleukin 1 (IL-I), IL-2, IL-4, interferon (IFN-gamma), tumor necrosis factor beta, and transforming growth factor beta1 (TGF-beta1). The bile duct epithelial cells strongly expressed HLA-ABC in all cases, CD56 in 47 of 55, IL-4 in 15 of 41, TGF-beta1 in 14 of 25, and CD29 in 4 of 25 cases. The other markers including IFN-gamma, HLA-DR, HLA-DP, and HLA-DQ were not expressed by bile duct cells. The expression of HLA class I agrees with previous observations while the absence of class II expression does not. The expression by the bile duct epithelium of CD56 confirms our own previous report. A new observation is the finding of molecules such as IL-4, TGF-beta1, and CD29 strongly expressed in the bile ducts cells. The presence of these molecules, taken together with the lack of IFN-gamma expression, contradicts previous speculations that attributed to IFN-gamma a role in the induction of major histocompatibility antigens and adhesion molecules in immune-mediated alcoholic liver disease.
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PMID:The antigenic heterogeneity of the bile duct epithelium in alcoholic liver disease. VA Cooperative Study Group 275. 1023 99

An improved ability to monitor hepatitis C virus (HCV)-specific T cell immunity in infected patients may provide novel information regarding the pathogenesis and prognosis of this infection. We used an ELISPOT assay to analyze a cross-section of HCV-infected humans. HCV-infected patients without cirrhosis, those with cirrhosis, and controls with other liver diseases were tested for recall responses to HCV Core and NS3 proteins. Peripheral blood lymphocytes (PBLs) from HCV-infected patients without cirrhosis responded to NS3 and Core proteins, producing predominantly IFN-gamma, with little IL-4 or IL-5. In contrast, PBLs from HCV-infected patients with cirrhosis responded to NS3, but not to the Core protein, suggesting a selectively altered immune state during cirrhosis. Our data provide support for the notion that HCV-specific IFN-gamma-producing immunity is important in the pathogenesis of progressing HCV-related disease.
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PMID:ELISPOT analysis of hepatitis C virus protein-specific IFN-gamma-producing peripheral blood lymphocytes in infected humans with and without cirrhosis. 1131 95

The pro-inflammatory interleukines play a major role in the progress of chronic hepatitis C. Among the patients with chronic hepatitis C virus (HCV) infection, the morphology of the liver was assessed and the levels of serum and liver-tissue IL-1beta, IL-4 and IL-6 were determined. The levels of the cytokines were related to the liver-tissue changes. RNA-HCV was measured by the RT-PCR method. Cytokine levels of the serum and liver tissue were measured by the Quantikine High Sensitivity test. The levels of serum IL-1beta, IL-4 and IL-6 (0.221, 0.104 and 1.393 pg/ml) in all HCV patients were higher in comparison with healthy adults (0.188, 0.025 and 0.600 pg/ml). The levels of liver tissue IL-1beta, IL-4 and IL-6 (4291.3, p<0.05; 1624.6, p<0.05; 1158.7 pg/g protein) in all HCV patients were higher compared with patients with liver cirrhosis without HBV or HCV infection (2319.9, 553.6 and 756.2 pg/g protein). Patients with HCV infection demonstrated a significant correlation between serum and liver-tissue levels of IL-1beta (Pearson: 0.61, p<0.05) and IL-4 (Pearson: 0.51). The level of serum IL-6 in patients with moderate chronic active hepatitis was higher when compared with patients with mild chronic persistent hepatitis. Among the patients with mild chronic persistent hepatitis, the levels of liver-tissue IL-6 were higher compared with those with moderate chronic active hepatitis. There was no correlation between histology changes and the levels of serum and liver-tissue IL-1beta and IL-4.
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PMID:The levels of IL-1beta, IL-4 and IL-6 in the serum and the liver tissue of chronic HCV-infected patients. 1172 34

Fibrosis is a pathologic process, which includes scar formation and over production of extracellular matrix, by the connective tissue, as a response to tissue damage. The molecular process is not different from normal formation of connective tissue and extracellular matrix in the normal organs. The context, the environment and the over production make the difference. Fibrosis formation includes interaction between many cell types and cytokines, and when the balance becomes profibrotic, there is fibrosis formation. Major profibrotic agents are type 2 CD4 positive lymphocytes, CD40 receptor and ligand interaction, and the following cytokines: IL-4, transforming growth factor b, platelet derived growth factor. The major antifibrotic agent is interferon gamma. Pathologies include: in the skin pathologic scarring as colloid and hypertrophic scar, cirrhosis of liver and gallbladder, in the heart and the kidneys, pulmonary and bone-marrow fibrosis, and scleroderma. Scleroderma is chronic connective tissue disease, expressed clinically by systemic sclerosis and diffuses fibrosis of the skin and viscera. This is a progressive degenerative disorder of the blood vessels, skin, lungs, kidneys, heart and GI tract and for this reason this disease plays a major role in fibrosis research. Fibrosis is considered an irreversible process, at least clinically, and is usually treated by anti-inflammatory and immunosuppressive agents. This kind of therapy was not proven successful and sometimes it harms more than cures. Many patients suffer from fibrotic diseases and the aim is to develop anti-fibrotic agents, targeted to the pathologic molecular process. Progressing step by step in this issue has direct clinic affect.
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PMID:[Fibrotic diseases]. 1247 33

IL-18 is a pleiotropic cytokine and is produced by various types of cells including activated macrophages, particularly Kupffer cells. IL-18 has potential to activate inflammatory responses through induction of IFN-gamma production in collaboration with IL-12. Somewhat paradoxically, IL-18 also has the capacity to induce allergic responses via induction of IL-4 production by T helper cells and to activate mast cells and basophils to release atopic effector molecules such as histamine. Indeed, IL-18 is involved in inflammatory tissue injuries, such as Crohn's disease and atherosclerosis, and also in hyper IgE and atopic dermatitis. IL-18 is particularly important for induction of experimental liver diseases. Endotoxin-induced liver injury or Fas ligand-induced hepatitis is caused by endogenous IL-18 in mice. Moreover, patients with liver diseases such as fulminant hepatitis, liver cirrhosis due to hepatitis virus infection and primary biliary cirrhosis show elevation of serum levels of IL-18, that correlates with the corresponding disease severity. Therefore, endogenous IL-18 plays a major role in induction of some types of liver injuries in mice and human. NKT cells that express both T cell receptor and NK cell marker are abundant in the liver of mice and human. Recent studies have revealed that NKT cells participate in some types of liver injuries, such as concanavalin A-induced T cell-mediated hepatitis and malaria hepatitis. In this review article, we focus on IL-18-involving liver damages and NKT-cell-mediated liver injuries.
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PMID:Cytokine-induced inflammatory liver injuries. 1452 86

The cytokine profiles were investigated in 171 patients with chronic hepatitis (CH) and in 173 patients with liver cirrhosis (LC). Increasing mean concentrations of IFN-alpha, TNF-alpha, IL-4 and IL-6 in blood serum as well as of the functional (antiviral and cytolytic) activity of IFN-alpha and TNF-alpha were found to be typical of a majority of CH and LC patients. Higher concentrations of IFN-alpha, IL-1, TNF-alpha and IL-6 in blood serum of CH patients are more typical of viral hepatitis versus alcoholic one. The replicative activity of hepatotropic viruses induces a powerful cytokine response. The LC etiology did not have any essential impact, in a majority of cases, on the blood-serum cytokine profile. A low function activity of TNF-alpha in blood serum signifies that the biological effects of the above cytokine are blocked. Finally, such analysis of the parameters of concentrations and functional activity of serum cytokines ensures a more objective evaluation of the pathogenetic disease mechanism and provides for prognosticating its outcome.
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PMID:[The role of cytokines and interferon-alpha in the pathogenesis of chronic diffuse diseases of the liver]. 1515 24


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