thymosin and Liver-Diseases

Liver fibrosis, a major characteristic of chronic liver disease, is inappropriate tissue remodeling caused by prolonged parenchymal cell injury and inflammation. During liver injury, hepatic stellate cells (HSCs) undergo transdifferentiation from quiescent HSCs into activated HSCs, which promote the deposition of extracellular matrix proteins, leading to liver fibrosis. Thymosin beta 4 (Tβ4), a major actin-sequestering protein, is the most abundant member of the highly conserved β-thymosin family and controls cell morphogenesis and motility by regulating the dynamics of the actin cytoskeleton. Tβ4 is known to be involved in various cellular responses, including antiinflammation, wound healing, angiogenesis, and cancer progression. Emerging evidence suggests that Tβ4 is expressed in the liver; however, its biological roles are poorly understood. Herein, we introduce liver fibrogenesis and recent findings regarding the function of Tβ4 in various tissues and discuss the potential role of Tβ4 in liver fibrosis with a special focus on the effects of exogenous and endogenous Tβ4. Recent studies have revealed that activated HSCs express Tβ4 in vivo and in vitro. Treatment with the exogenous Tβ4 peptide inhibits the proliferation and migration of activated HSCs and reduces liver fibrosis, indicating it has an antifibrotic action. Meanwhile, the endogenously expressed Tβ4 in activated HSCs is shown to promote HSCs activation. Although the role of Tβ4 has not been elucidated, it is apparent that Tβ4 is associated with HSC activation. Therefore, understanding the potential roles and regulatory mechanisms of Tβ4 in liver fibrosis may provide a novel treatment for patients.

Topics: Cell Physiological Phenomena; Cell Transdifferentiation; Gene Expression; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Signal Transduction; Thymosin

Thymalfasin (thymosin-alpha 1) is an immunomodulating agent able to enhance the Th1 immune response. It has been evaluated for its immunomodulatory activities and related therapeutic potential in several diseases, including chronic hepatitis B and C, AIDS, primary immunodeficiency diseases, depressed response to vaccination and cancer. The basis for effectiveness in these conditions is primarily through modulation of immunological responsiveness, as thymalfasin has been shown to have beneficial effects on numerous immune system parameters and to increase T-cell differentiation and maturation. Thymalfasin is responsible for reconstitution of immune function when thymic tissue is given back to thymectomized animals. In addition, thymalfasin has been shown to have efficacy in multiple experimental models of immune dysfunction, mainly, infectious diseases such as hepatitis (woodchuck) and influenza (mouse), and cancer such as melanoma (mouse) and colorectal carcinoma (rat) where thymalfasin has shown antitumor effects.

Topics: Amino Acid Sequence; Animals; Antiviral Agents; Apoptosis; Cytokines; Histocompatibility Antigens Class I; Humans; Immunologic Factors; Liver Diseases; Lymphocytes; Lymphopoiesis; Molecular Sequence Data; Thymalfasin; Thymosin; Virus Replication

Thymalfasin (thymosin-alpha 1) is an immunomodulating agent able to enhance the Thl immune response. It has been evaluated for its immunomodulatory activities and related therapeutic potential in several diseases, including chronic hepatitis B and C, AIDS, primary immunodeficiency diseases, depressed response to vaccination and cancer. The basis for effectiveness in these conditions is primarily through modulation of immunological responsiveness, as thymalfasin has been shown to have beneficial effects on numerous immune system parameters and to increase T-cell differentiation and maturation. Thymalfasin is responsible for reconstitution of immune function when thymic tissue is given back to thymectomized animals. In addition, thymalfasin has been shown to have efficacy in multiple experimental models of immune dysfunction, mainly, infectious diseases such as hepatitis (woodchuck) and influenza (mouse), and cancer such as melanoma (mouse) and colorectal carcinoma (rat) where thymalfasin has shown antitumor effects.

Topics: Adjuvants, Immunologic; Humans; Liver Diseases; Thymalfasin; Thymosin; Virus Diseases

Although the various biological roles of thymosin β4 (Tβ4) have been studied widely, the effect of Tβ4 and Tβ4-expressing cells in the liver remains unclear. Therefore, we investigated the expression and function of Tβ4 in chronically damaged livers. CCl4 was injected into male mice to induce a model of chronic liver disease. Mice were sacrificed at 6 and 10 weeks after CCl4 treatment, and the livers were collected for biochemical analysis. The activated LX-2, human hepatic stellate cell (HSC) line, were transfected with Tβ4-specific siRNA and activation markers of HSCs were examined. Compared to HepG2, higher expression of Tβ4 in RNA and protein levels was detected in the activated LX-2. In addition, Tβ4 was up-regulated in human liver with advanced liver fibrosis. The expression of Tβ4 increased during mouse HSC activation. Tβ4 was also up-regulated and Tβ4-positive cells were co-localized with α-smooth muscle actin (α-SMA) in the livers of CCl4-treated mice, whereas such cells were rarely detected in the livers of corn-oil treated mice. The suppression of Tβ4 in LX-2 cells by siRNA induced the down-regulation of HSC activation-related genes, tgf-β, α-sma, collagen, and vimentin, and up-regulation of HSC inactivation markers, ppar-γ and gfap. Immunofluorescent staining detected rare co-expressing cells with Tβ4 and α-SMA in Tβ4 siRNA-transfected cells. In addition, cytoplasmic lipid droplets were observed in Tβ4 siRNA-treated cells. These results demonstrate that activated HSCs expressed Tβ4 in chronically damaged livers, and this endogenous expression of Tβ4 influenced HSC activation, indicating that Tβ4 might contribute to liver fibrosis by regulating HSC activation.

Topics: Cell Line; Hepatic Stellate Cells; Humans; Liver Diseases; Thymosin

In vitro IgG synthesis by peripheral blood mononuclear cells (PBM) from patients with chronic liver disease (CLD) was studied. In addition, the effect of pokeweed mitogen (PWM), polyadenylic-polyuridylic acid complexes (poly A:U) and thymosin fraction 5 on IgG synthesis was determined. Unstimulated cultures of PBM from patients with chronic active hepatitis (CAH) and alcoholic cirrhosis (AC) synthesized significantly higher quantities of IgG than the controls. Moreover, there was a direct correlation between serum IgG concentrations and the quantity of newly synthesized IgG in these unstimulated cultures. PWM, poly A:U and thymosin each stimulated increased IgG synthesis in the controls. While neither poly A:U nor thymosin enhanced IgG synthesis in patients with CLD, PWM increased IgG synthesis in CAH but not AC. These results indicate that spontaneous in vitro B cell synthesis of IgG is enhanced in CLD and may reflect antigenic stimulation in vivo.

Topics: Adult; Aged; B-Lymphocytes; Chronic Disease; Female; Hepatitis; Humans; Hypergammaglobulinemia; Immunoglobulin G; Liver Cirrhosis, Alcoholic; Liver Diseases; Male; Middle Aged; Pokeweed Mitogens; Poly A-U; Thymosin

Topics: Adult; Aged; Animals; Antibody-Dependent Cell Cytotoxicity; Cytotoxicity, Immunologic; Female; Hepatitis; Hepatitis, Alcoholic; Humans; Immunity, Cellular; Liver Cirrhosis, Alcoholic; Liver Diseases; Lymphocytes; Male; Middle Aged; Rats; Thymosin; Time Factors

Mature T lymphocyte concentrations are reduced, null cell concentrations are increased, and Fc receptor bearing (B and K) lymphocyte concentrations are normal, in the peripheral blood of patients with chronic hepatocellular or cholestatic liver disease. Some null cells can be stimulated by either thymosin or levamisole to form rosettes with sheep erythrocytes. These changes are present in viral, alcohol associated and 'autoimmune' liver disease and are therefore probably secondary phenomena relating to liver damage.

Topics: Adult; Female; Hepatitis; Hepatitis B Antigens; Humans; Leukocyte Count; Levamisole; Liver Cirrhosis, Biliary; Liver Diseases; Lymphocytes; Male; Middle Aged; T-Lymphocytes; Thymosin