tretinoin and Hepatitis

Quiescent hepatic stellate cells (HSCs) in healthy liver store 80% of total liver retinols and release them depending on the extracellular retinol status. However, HSCs activated by liver injury lose their retinols and produce a considerable amount of extracellular matrix, subsequently leading to liver fibrosis. Emerging evidence suggests that retinols and their metabolites such as retinoic acids (RAs) contribute to liver regeneration, fibrosis and tumor. However, it is not clear yet why HSCs lose retinol, which enzymes are involved in the retinol metabolism of HSCs and what function of retinol metabolites on HSCs upon liver injury. Recently, our group and collaborators have demonstrated that during activation, HSCs not only lose retinols but also metabolize them into RAs by alcohol dehydrogenases and retinaldehyde dehydrogenases. As transcriptional factors, metabolized RAs induce retinoic acid early inducible-1 and suppressor of cytokine signaling 1 in HSCs, which plays an important role in the interaction between HSCs and natural killer cells. In addition, RAs released from HSCs may induce hepatic cannabinoid receptor 1 expression in alcoholic liver steatosis or regulate immune responses upon liver inflammation. The present review summarizes the role of endogenous metabolized RAs on HSCs themselves and on other liver cells including hepatocytes and immune cells. Moreover, the effects of exogenous retinol and RA treatments on HSCs and liver disease are discussed.

Topics: Animals; Carcinoma, Hepatocellular; Extracellular Matrix; Fatty Liver; Hepatic Stellate Cells; Hepatitis; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Liver Regeneration; Tretinoin; Vitamin A

Immune mediated liver injury includes activation of different immune pathways that requires various modalities to control their consequences. The current study involves evaluation of retinoic acid (RA) modulatory effects on immune responses induced in concanavalin A (ConA) model of acute hepatitis.. Mice were divided as follows: Control group; RA group: received 35 mg/kg RA; ConA group: received 15 mg/kg ConA; ConA + RA group: received ConA and RA as described. Liver function biomarkers were measured in addition to malondialdehyde as lipid peroxidation biomarker. Liver tissue sections were scored for necro-inflammation, neutrophils infiltration, CD4+ T cells infiltration and NF-κb positive cells. Effect on hepatic levels of TNF-α, IL-4, IL-10 and MCP-1 was evaluated as well.. Injection of RA before ConA significantly (p < 0.001) decreased ALT, AST and LDH levels compared to their levels in ConA group. Hepatic infiltration of neutrophils and CD4+ T cells was markedly (p < 0.001) reduced by RA. Hepatic injury, necrosis and expression of NF-κb were significantly decreased by RA when injected before ConA challenge. A significant decrease in the measured cytokines TNF-α and IL-4 was observed in ConA + RA group in addition to a decrease in MCP-1 level. On the other hand, IL-10 was significantly increased in the latter group compared to ConA group.. RA can protect against ConA-induced hepatitis through: interrupting early inflammatory response as neutrophils, monocytes and CD4+ T cells infiltration, modulating IL-4 level and subsequent production of TNF-α and NF-κb activation, mitigating second inflammatory responses through increasing IL-10 liver production.

Topics: Animals; Anti-Inflammatory Agents; CD4-Positive T-Lymphocytes; Chemical and Drug Induced Liver Injury; Concanavalin A; Cytokines; Hepatitis; Liver; Male; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Signal Transduction; Tretinoin

Retinoic acid (RA) is a diverse regulator of immune responses. Although RA promotes natural killer T (NKT) cell activation in vitro by increasing CD1d expression on antigen-presenting cells (APCs), the direct effects of RA on NKT-cell responses in vivo are not known. In the present study, we demonstrated the effect of RA on the severity of Con A-induced hepatitis and molecular changes of NKT cells. First, we demonstrated that Con A-induced liver damage was ameliorated by RA. In correlation with cytokine levels in serum, RA regulated the production of IFN-γ and IL-4 but not TNF-α by NKT cells without influencing the NKT-cell activation status. However, RA did not alleviate α-GalCer-induced liver injury, even though it reduced IFN-γ and IL-4 but not TNF-α levels in serum. This regulation was also detected when liver mononuclear cells (MNCs) or NKT hybridoma cells were treated with RA in vitro. The regulatory effect of RA on NKT cells was mediated by RAR-α, and RA reduced the phosphorylation of MAPK. These results suggest that RA differentially modulates the production of effector cytokines by NKT cells in hepatitis, and the suppressive effect of RA on hepatitis varies with the pathogenic mechanism of liver injury.

Topics: Animals; Blotting, Western; Concanavalin A; Disease Models, Animal; Female; Galactosylceramides; Gene Expression Regulation; Hepatitis; Interferon-gamma; Interleukin-4; Kaplan-Meier Estimate; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Natural Killer T-Cells; Real-Time Polymerase Chain Reaction; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; RNA; Specific Pathogen-Free Organisms; Tretinoin; Tumor Necrosis Factor-alpha

Retinoic acid (RA), which is the biologically active form of vitamin A, acts through the nuclear hormone receptor RAR (RA receptor) to induce either gene activation or repression. RA production and its effects have been linked to macrophages, dendritic cells, T and B cells, and iNKT cells in the immune system and play pro- as well as anti-inflammatory roles depending on the cell type and the immune context. In this issue of the European Journal of Immunology, Lee et al. [Eur. J. Immunol. 2012. 42: 1685-1694] show that RA ameliorates Con A-induced murine hepatitis by selectively downmodulating IFN-γ and IL-4 production in disease-causing NKT cells in the liver. Remarkably, this effect is restricted to this liver disease model and does not apply to αGalCer-induced murine liver injury, which is driven by other cytokines. The study identifies retinoid signaling as an important endogenous mechanism controlling immune reactions and also as a potential pharmacological target for treatment of hepatic liver injury. Furthermore, the study by Lee et al. provides additional support for the concept of metabolic regulation of immune function.

Topics: Animals; Daucus carota; Diet; Hepatitis; Mice; Natural Killer T-Cells; Tretinoin