59 research outputs found
cis-Urocanic Acid Attenuates Acute Dextran Sodium Sulphate-Induced Intestinal Inflammation
On exposure to sunlight, urocanic acid (UCA) in the skin is converted from trans to the cis form and distributed systemically where it confers systemic immunosuppression. The aim of this study was to determine if administration of cis-UCA would be effective in attenuating colitis and the possible role of IL-10. Colitis was induced in 129/SvEv mice by administering 5% dextran sodium sulfate (DSS) for 7 days in drinking water. During this period mice received daily subcutaneously injections of cis-UCA or vehicle. To examine a role for IL-10, 129/SvEv IL-10−/− mice were injected for 24 days with cis-UCA or vehicle. Clinical disease was assessed by measurement of body weight, stool consistency, and presence of blood. At sacrifice, colonic tissue was collected for histology and measurement of myeloperoxidase and cytokines. Splenocytes were analyzed for CD4+CD25+FoxP3+ T-regulatory cells via flow cytometry. Murine bone-marrow derived antigen-presenting cells were treated with lipopolysaccharide (LPS) ± UCA and cytokine secretion measured. Our results demonstrated that cis-UCA at a dose of 50 µg was effective in ameliorating DSS-induced colitis as evidenced by reduced weight loss and attenuated changes in colon weight/length. This protection was associated with reduced colonic expression of CXCL1, an increased expression of IL-17A and a significant preservation of splenic CD4+CD25+FoxP3+ T-regulatory cells. cis-UCA decreased LPS induced CXCL1, but not TNFα secretion, from antigen-presenting cells in vitro. UCA reduced colonic levels of IFNγ in IL-10−/− mice but did not attenuate colitis. In conclusion, this study demonstrates that cis-urocanic acid is effective in reducing the severity of colitis in a chemically-induced mouse model, indicating that pathways induced by ultraviolet radiation to the skin can influence distal sites of inflammation. This provides further evidence for a possible role for sunlight exposure in modulating inflammatory disorders
Long-Lived Plasma Cells and Memory B Cells Produce Pathogenic Anti-GAD65 Autoantibodies in Stiff Person Syndrome
Stiff person syndrome (SPS) is a rare, neurological disorder characterized by sudden cramps and spasms. High titers of enzyme-inhibiting IgG autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GAD65) are a hallmark of SPS, implicating an autoimmune component in the pathology of the syndrome. Studying the B cell compartment and the anti-GAD65 B cell response in two monozygotic twins suffering from SPS, who were treated with the B cell-depleting monoclonal anti-CD20 antibody rituximab, we found that the humoral autoimmune response in SPS is composed of a rituximab-sensitive part that is rapidly cleared after treatment, and a rituximab-resistant component, which persists and acts as a reservoir for autoantibodies inhibiting GAD65 enzyme activity. Our data show that these potentially pathogenic anti-GAD65 autoantibodies are secreted by long-lived plasma cells, which may either be persistent or develop from rituximab-resistant memory B lymphocytes. Both subsets represent only a fraction of anti-GAD65 autoantibody secreting cells. Therefore, the identification and targeting of this compartment is a key factor for successful treatment planning of SPS and of similar autoimmune diseases
The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury
10.1371/journal.pone.0075483PLoS ONE810-POLN
Pharmacological Characterization of [<sup>3</sup>H]ATPCA as a Substrate for Studying the Functional Role of the Betaine/GABA Transporter 1 and the Creatine Transporter
The
betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT1)
is one of the four GABA transporters (GATs) involved in the termination
of GABAergic neurotransmission. Although suggested to be implicated
in seizure management, the exact functional importance of BGT1 in
the brain is still elusive. This is partly owing to the lack of potent
and selective pharmacological tool compounds that can be used to probe
its function. We previously reported the identification of 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic
acid (ATPCA), a selective substrate for BGT1 over GAT1/GAT3, but also
an agonist for GABA<sub>A</sub> receptors. With the aim of providing
new functional insight into BGT1, we here present the synthesis and
pharmacological characterization of the tritiated analogue, [<sup>3</sup>H]ATPCA. Using traditional uptake assays at recombinant transporters
expressed in cell lines, [<sup>3</sup>H]ATPCA displayed a striking
selectivity for BGT1 among the four GATs (<i>K</i><sub>m</sub> and <i>V</i><sub>max</sub> values of 21 μM and 3.6
nmol ATPCA/(min × mg protein), respectively), but was also found
to be a substrate for the creatine transporter (CreaT). In experiments
with mouse cortical cell cultures, we observed a Na<sup>+</sup>-dependent
[<sup>3</sup>H]ATPCA uptake in neurons, but not in astrocytes. The
neuronal uptake could be inhibited by GABA, ATPCA, and a noncompetitive
BGT1-selective inhibitor, indicating functional BGT1 in neurons. In
conclusion, we report [<sup>3</sup>H]ATPCA as a novel radioactive
substrate for both BGT1 and CreaT. The dual activity of the radioligand
makes it most suitable for use in recombinant studies
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