Article

The gap-junction inhibitor carbenoxolone suppresses the differentiation of Th17 cells through inhibition of IL-23 expression in antigen presenting cells.

Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Journal of neuroimmunology (Impact Factor: 2.84). 12/2011; 240-241:58-64. DOI: 10.1016/j.jneuroim.2011.09.012
Source: PubMed

ABSTRACT Carbenoxolone (CBX) is a widely used gap-junction inhibitor. We have previously shown that treatment with CBX significantly delayed the onset of experimental autoimmune encephalomyelitis (EAE). However, the mechanism by which CBX delays the onset of EAE remains to be elucidated. Here, we show that CBX specifically inhibits the production of IL-23 by dendritic cells (DCs) and microglia in vitro. CBX treatment significantly reduced the population of Th17 cells in EAE mice. Furthermore, CBX downregulated the expression of IL-23 p19 via increased production of protein phosphatase 2A (PP2A). Thus, CBX may be an effective therapeutic strategy against Th17-mediated autoimmune diseases, such as multiple sclerosis.

0 Bookmarks
 · 
136 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin-34 (IL-34) is a newly discovered cytokine as an additional ligand for colony stimulating factor-1 receptor (CSF1R), and its functions are expected to overlap with colony stimulating factor-1/macrophage-colony stimulating factor. We have previously shown that the IL-34 is primarily produced by neurons in the central nervous system (CNS) and induces proliferation and neuroprotective properties of microglia which express CSF1R. However, the functions of IL-34 in the CNS are still elucidative. Here we show that CNS capillary endothelial cells also express CSF1R. IL-34 protected blood–brain barrier integrity by restored expression levels of tight junction proteins, which were downregulated by pro-inflammatory cytokines. The novel function of IL-34 on the blood–brain barrier may give us a clue for new therapeutic strategies in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease.
    PLoS ONE 12/2014; 9(12):e115981. · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS), neuromyelitis optica (NMO) and Baló's disease (BD) are inflammatory demyelinating diseases of the central nervous system (CNS). We previously reported aquaporin-4 (AQP4) loss without perivascular deposition of complement or immunoglobulin in demyelinating diseases, suggesting that astrocytic damage could be a common denominator in heterogeneous demyelinating conditions. To investigate the relationship between astrocytopathy and demyelination, we focused on connexins (Cxs), which form gap junction channels between astrocytes and oligodendrocytes, and maintain myelination and homeostasis in the CNS. We pathologically evaluated the expression of astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 in autopsied tissue samples from MS, NMO and BD patients. In all BD samples, astrocytic Cx43 and oligodendrocytic Cx32/Cx47 expression was diminished in both demyelinated and preserved myelin layers. In the leading edge of BD lesions, Cx43 and AQP4 loss preceded Cx32/Cx47 loss. Half of the NMO and MS samples showed preferential loss of astrocytic Cx43 in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte-oligodendrocyte gap junctions were lost. Cases with Cx43 loss were significantly associated with rapid disease progression (death within 2 years after onset), regardless of the disease phenotype. Pathologically, Cx43 loss was frequently accompanied by distal oligodendrogliopathy. These findings suggest that Cx43 astrocytopathy can occur in MS, BD and NMO. Furthermore, astrocytic Cx43 loss might be associated with disease aggressiveness and distal oligodendrogliopathy, not only in BD,but also MS and NMO. Early disruption of astrocytic foot processes could precede demyelination and contribute to the pathogenesis of demyelinating disorders.
    Clinical and Experimental Neuroimmunology. 12/2013; 4(s1).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autocrine and paracrine signals coordinate responses of several cell types of the immune system that provide efficient protection against different challenges. Antigen-presenting cells (APCs) coordinate activation of this system via homocellular and heterocellular interactions. Cytokines constitute chemical intercellular signals among immune cells and might promote pro- or anti-inflammatory effects. During the last two decades, two membrane pathways for intercellular communication have been demonstrated in cells of the immune system. They are called hemichannels (HCs) and gap junction channels (GJCs) and provide new insights into the mechanisms of the orchestrated response of immune cells. GJCs and HCs are permeable to ions and small molecules, including signaling molecules. The direct intercellular transfer between contacting cells can be mediated by GJCs, whereas the release to or uptake from the extracellular milieu can be mediated by HCs. GJCs and HCs can be constituted by two protein families: connexins (Cxs) or pannexins (Panxs), which are present in almost all APCs, being Cx43 and Panx1 the most ubiquitous members of each protein family. In this review, we focus on the effects of different cytokines on the intercellular communication mediated by HCs and GJCs in APCs and their impact on purinergic signaling.
    Mediators of Inflammation 01/2014; 2014:742734. · 3.88 Impact Factor

Full-text

Download
0 Downloads
Available from
Dec 15, 2014