Pioglitazone-Mediated Peroxisome Proliferator-Activated Receptor γ Activation Aggravates Murine Immune-Mediated Hepatitis.

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) regulates target gene expression upon ligand binding. Apart from its effects on metabolism, PPARγ activity can inhibit the production of pro-inflammatory cytokines by several immune cells, including dendritic cells and macrophages. In chronic inflammatory disease models, PPARγ activation delays the onset and ameliorates disease severity.

Prenatal acetaminophen induces liver toxicity in dams, reduces fetal liver stem cells, and increases airway inflammation in adult offspring.

Background & Aims: During pregnancy, acetaminophen is one of the very few medications recommended by physicians to treat fever or pain. Recent insights from epidemiological studies suggest an association between prenatal acetaminophen medication and an increased risk for development of asthma in children later in life. The underlying pathogenesis of such association is still unknown.

Hepatocytes induce Foxp3⁺ regulatory T cells by Notch signaling.

The liver plays a pivotal role in maintaining immunological tolerance, although the exact molecular mechanism is still largely unknown. The induction of systemic tolerance by liver resident APCs has been attributed to peripheral deletion and to the induction of Tregs. HCs, the parenchymal cells in the liver, could function as nonprofessional APCs and interact and establish cell-cell contact with T lymphocytes.

Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells.

The "liver tolerance effect" has been attributed to a unique potential of liver-resident nonprofessional APCs including hepatocytes (HCs) to suppress T cell responses. The exact molecular mechanism of T cell suppression by liver APCs is still largely unknown. In mice, IL-10-dependent T cell suppression is observed after Th1-mediated hepatitis induced by Con A.

Regulatory T cell-derived IL-10 ameliorates crescentic GN.

Regulatory T cells (Tregs) exert their immunosuppressive activity through several immunoregulatory mechanisms, including the production of anti-inflammatory cytokines such as IL-10. Although several studies suggest a role for Tregs in modulating crescentic GN, the underlying mechanisms are not well understood. Here, using IL-10 reporter mice, we detected IL-10-producing Foxp3(+) T cells in the kidney, blood, and secondary lymphoid tissue in a mouse model of crescentic GN.

Acetaminophen and pregnancy: short- and long-term consequences for mother and child.

Counter-intuitively, over-the-counter medication is commonly taken by pregnant women. In this context, acetaminophen (APAP, e.g.

Sharpin contributes to TNFα dependent NFκB activation and anti-apoptotic signalling in hepatocytes.

TNFα stimulates both pro- and anti-apoptotic signalling in hepatocytes. Anti-apoptotic signalling depends on a cascade of ubiquitylation steps leading to NFκB activation. Using Sharpin-deficient mice, we show that the ubiquitin binding protein Sharpin interacts with Hoip, an E3 ligase which generates linear ubiquitin chains.

Induction of heme oxygenase 1 prevents progression of liver fibrosis in Mdr2 knockout mice.

Unlabelled: Induction or overexpression of the heme-degrading enzyme, heme oxygenase 1 (HO-1), has been shown to protect mice from liver damage induced by acute inflammation. We have investigated the effects of HO-1 induction in a mouse model of chronic liver inflammation and fibrogenesis with progression to hepatocellular carcinoma (HCC) (Mdr2ko; FVB.129P2-Abcb4(tm1Bor)).

Regulatory T cells control the Th1 immune response in murine crescentic glomerulonephritis.

Crescentic glomerulonephritis is mediated by inappropriate humoral and cellular immune responses toward self-antigens that may result from defects in central and peripheral tolerance. Evidence now suggests that regulatory T cells (Tregs) may be of pathophysiological importance in proliferative and crescentic forms of glomerulonephritis. To analyze the role of endogenous Tregs in a T cell-dependent glomerulonephritis model of nephrotoxic nephritis, we used 'depletion of regulatory T cell' (DEREG) mice that express the diphtheria toxin receptor under control of the FoxP3 (forkhead box P3) gene promoter.

Transcription factor Fra-1 induces cholangitis and liver fibrosis.

Unlabelled: Chronic diseases of the biliary system are common and may cause fibrosis and eventually progression to liver cirrhosis. The aim was to define a new mouse model of a cholangiopathy leading to liver fibrosis in fra-1tg mice. Liver pathology of fra-1tg mice was analyzed in detail by histology and flow cytometry.

CXCR3 deficiency exacerbates liver disease and abrogates tolerance in a mouse model of immune-mediated hepatitis.

The chemokine receptor CXCR3 is preferentially expressed by Th1 cells and critically involved in their recruitment to inflamed tissue. In a mouse model of immune-mediated liver injury inducible by Con A, we investigated the role of CXCR3 in acute IFN-γ-mediated hepatitis as well as in tolerance induction, which has been shown to depend on IL-10-producing CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Induction of Con A hepatitis resulted in increased intrahepatic expression of the CXCR3 ligands CXCL9, CXCL10, and CXCL11.

Tolerance induction in response to liver inflammation.

Background/aims: The liver plays an important role in immunological tolerance due to its anatomical location, as it links the gastrointestinal tract and the systemic venous circulation. Therefore, immune reactions against dietary or bacterial antigens from the gut have to be avoided. However, immune responses resulting in elimination of harmful hepatotrophic pathogens have to be induced.

CCR6 recruits regulatory T cells and Th17 cells to the kidney in glomerulonephritis.

T cells recruited to the kidney contribute to tissue damage in crescentic and proliferative glomerulonephritides. Chemokines and their receptors regulate T cell trafficking, but the expression profile and functional importance of chemokine receptors for renal CD4+ T cell subsets are incompletely understood. In this study, we observed that renal FoxP3+CD4+ regulatory T cells (Tregs) and IL-17-producing CD4+ T (Th17) cells express the chemokine receptor CCR6, whereas IFNgamma-producing Th1 cells are CCR6-.

The neuropeptide calcitonin gene-related peptide (CGRP) prevents inflammatory liver injury in mice.

Background/aims: Calcitonin gene-related peptide (CGRP) is a potent vasodilator and supposed to be responsible for neurogenic inflammation involved in migraine. Its role in inflammatory diseases of other organs is controversial and poorly investigated regarding liver inflammation, although the organ is innervated by CGRP containing primary sensory nerve fibers.

Methods: Male Balb/c and IL-10(-/-) mice were pretreated with either alphaCGRP or the CGRP receptor antagonists CGRP(8-37) or BIBN4096BS.

Down-regulation of the de-ubiquitinating enzyme ubiquitin-specific protease 2 contributes to tumor necrosis factor-alpha-induced hepatocyte survival.

Tumor necrosis factor-alpha (TNFalpha) stimulation of hepatocytes induces either cell survival or apoptosis, which seems to be regulated by the ubiquitin-proteasome system. Here we investigated the role of TNFalpha-induced down-modulation of the de-ubiquitinating enzyme USP2 for hepatocyte survival. Inhibition of hepatocyte apoptosis by pre-treatment with TNFalpha (TNFalpha tolerance) was analyzed in the mouse model of galactosamine/TNFalpha-induced liver injury and in actinomycin D/TNFalpha-treated primary mouse hepatocytes.

IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice.

Unlabelled: The liver appears to play an important role in immunological tolerance, for example, during allo-transplantation. We investigated tolerance mechanisms in the model of concanavalin A (ConA)-induced immune-mediated liver injury in mice. We found that a single injection of a sublethal ConA dose to C57BL/6 mice induced tolerance toward ConA-induced liver damage within 8 days.