concanavalin-a and Cholestasis

Patients with inflammatory liver disease commonly develop debilitating symptoms, called sickness behaviors, which arise via changes in brain function. Monocytes that produce tumor necrosis factor interact with cerebral endothelial cells to activate microglial cells and promote sickness behavior. Platelets regulate inflammation, and aggregates of monocytes and platelets are increased in the circulation of patients with liver disease. We investigated the role of platelets in inducing inflammatory features of circulating monocytes and promoting sickness behaviors in mice with cholestatic liver injury.. We performed bile-duct ligations or sham surgeries on C57BL/6 or toll-like receptor 4 (TLR4)-knockout mice to induce liver inflammation. Liver inflammation was also induced in a separate group of mice by administration of concanavalin A. Circulating platelets, aggregates of monocytes and platelets, and activation of microglial cells were measured by flow cytometry. To deplete platelets, mice were given anti-thrombocyte serum or normal rabbit serum (control) 4 days after surgery. Interactions between monocytes and cerebral endothelial cells were analyzed by intravital microscopy. Sickness behaviors were quantified based on time spent by adult mice engaging in social behaviors toward a juvenile mouse, compared with time spent in nonsocial behavior or remaining immobile.. Aggregates of monocytes and platelets in circulation of mice increased significantly following bile-duct ligation. Platelet-monocyte interactions were required for activation of inflammatory monocytes and production of tumor necrosis factor. Platelet depletion greatly reduced adhesive interactions between inflammatory monocytes and adhesive interactions with cerebral endothelial cells and activation of the microglia, as well as development of sickness behavior. Furthermore, TLR4 signaling was important for aggregation of monocytes and platelets, and development of sickness behavior following bile-duct ligation. These findings were confirmed in mice with concanavalin A-induced liver injury.. In mice with liver inflammation, we found TLR4 and aggregates of monocytes and platelets to regulate microglial activation and development of sickness behavior. These findings might lead to new therapeutic strategies for liver disease-associated symptoms.

Topics: Animals; Behavior, Animal; Blood Platelets; Chemical and Drug Induced Liver Injury; Cholestasis; Concanavalin A; Disease Models, Animal; Endothelial Cells; Illness Behavior; Male; Mice, Inbred C57BL; Mice, Knockout; Microglia; Monocytes; Platelet Activation; Social Behavior; Toll-Like Receptor 4

Periplakin (PPL) is a rod-shaped cytolinker protein thought to connect cellular adhesion junctional complexes to cytoskeletal filaments. PPL serves as a structural component of the cornified envelope in the skin and interacts with various types of proteins in cultured cells; its level decreases dramatically during tumorigenic progression in human epithelial tissues. Despite these intriguing observations, the physiological roles of PPL, especially in non-cutaneous tissues, are still largely unknown. Because we observed a marked fluctuation of PPL expression in mouse liver in association with the bile acid receptor farnesoid X receptor (FXR) and cholestasis, we sought to characterize the role of PPL in the liver and determine its contributions to the etiology and pathogenesis of cholestasis.. Time- and context-dependent expression of PPL in various mouse models of hepatic and renal disorders were examined by immunohistochemistry, western blotting, and quantitative real-time polymerase chain reactions.. The hepatic expression of PPL was significantly decreased in Fxr-/- mice. In contrast, the expression was dramatically increased during cholestasis, with massive PPL accumulation observed at the boundaries of hepatocytes in wild-type mice. Interestingly, the hepatic accumulation of PPL resulting from cholestasis was reversible. In addition, similar accumulation of PPL at cellular boundaries was found in epithelial cells around renal tubules upon ureteral obstruction.. PPL may be involved in the temporal accommodation to fluid stasis in different tissues. Further examination of the roles for PPL may lead to the discovery of a novel mechanism for cellular protection by cytolinkers that is applicable to many tissues and in many contexts.

Topics: Animals; Cholestasis; Concanavalin A; Epithelial Cells; Gene Expression; Hepatocytes; Kidney Tubules; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Plakins; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Ureteral Obstruction

Sepsis is a common and occasionally lethal complication of obstructive jaundice. The reasons for this increased susceptibility to infection are unknown. This study examines lymphocyte and reticuloendothelial (RES) function in animals with obstructive jaundice. Twelve New Zealand white rabbits (3-4 kg) were studied. Lymphocyte function was evaluated in six rabbits by phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM) stimulation. In six animals, hepatic RES function was assessed by calculating the phagocytic index (PI) using the disappearance of 99Tc sulfacolloid (5 mg/kg) iv. After baseline studies, the common bile duct was divided and ligated. The above studies and serum bilirubin were repeated at 3 weeks. Obstruction was then relieved by cholecystojejunostomy (CJ) and RES studies repeated monthly x 6. Preobstructive lymphocyte function showed a stimulation index ratio (log) of 0.85 +/- 0.25 for PHA, 0.75 +/- 0.3 for Con A, and 0.71 +/- 0.25 for PWM. With biliary obstruction, the values fell to -0.23 +/- 15 (P less than 0.006), -0.31 +/- 0.12 (P less than 0.006), and -0.29 (P less than 0.006), demonstrating impaired lymphocyte function. When tested lymphocytes were mixed with control pooled rabbit serum, however, no lymphocyte impairment was noted. Baseline hepatic PI was 6.02 +/- 0.18 and fell to 3.79 +/- 0.33 with obstruction (P less than .01) and remained low at (3.20 +/- 0.14) 1 month (P less than 0.01) and (3.33 +/- 0.23) at 3 months (P less than .01), after CJ but returned to normal (8.04 +/- 0.97) at 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cholestasis; Concanavalin A; Gallbladder; Jejunum; Kupffer Cells; Lymphocyte Activation; Lymphocytes; Male; Mononuclear Phagocyte System; Phagocytosis; Phytohemagglutinins; Pokeweed Mitogens; Rabbits

Techniques have been studied which distinguish two variants of human alpha-fetoprotein (AFP) on the basis of characteristics of the carbohydrate moiety of this glycoprotein. AFP in serum samples from six children with tumors of yolk sac origin showed little concanavalin-A (Con A) binding. In contrast, Con A binding of AFP was almost complete in serum samples from 14 other subjects with elevated AFP, including two with liver-cell tumors, eight with neonatal cholestasis, and four normal newborn infants. Differences were confirmed by immunoelectrophoretic studies. Thus, AFP from cells of yolk sac origin can be distinguished from AFP from liver cells or from tumors of hepatic cell origin.

Topics: alpha-Fetoproteins; Bile Ducts; Carcinoma, Hepatocellular; Child; Child, Preschool; Cholestasis; Chromatography, Affinity; Concanavalin A; Female; Hepatitis; Humans; Immunoelectrophoresis, Two-Dimensional; Infant; Infant, Newborn; Jaundice, Neonatal; Liver Neoplasms; Male; Mesonephroma; Pancreatic Neoplasms; Teratoma

Cell-mediated immune response was evaluated in 14 children with long-lasting intra- or extrahepatic cholestasis. Cell-mediated immunity was clearly depressed in children with intrahepatic cholestasis while children with extrahepatic biliary obstruction had a more modest and variable degree of impairment. This finding may be related to the longer duration of cholestasis and the higher total bile acid level in the intrahepatic compared to the extrahepatic group. In particular, in children with Byler disease, long-lasting, severe intrahepatic cholestasis was associated with depressed cell-mediated immunity and recurrent severe infections.

Topics: Adolescent; Child; Child, Preschool; Cholestasis; Chronic Disease; Concanavalin A; Female; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Infant; Lymphocyte Activation; Lymphocytes; Male; Phytohemagglutinins; Rosette Formation; Skin Tests

Topics: Breast Neoplasms; Cholestasis; Concanavalin A; Diagnosis, Differential; Digestive System Neoplasms; Female; Fetus; gamma-Glutamyltransferase; Humans; Isoenzymes; Kidney Diseases; Liver Diseases; Pregnancy