Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro
| Autor: | Tomoaki Komai, Yoshifumi Fujita, Tomiichiro Oda, Harumi Kuwabara, Yoshiko Onozawa, Miyuki Nagasaki |
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| Rok vydání: | 2011 |
| Předmět: |
Agonist
Male medicine.drug_class medicine.medical_treatment T cell T-Lymphocytes Inflammation CHO Cells Biology Receptors G-Protein-Coupled Small Molecule Libraries Mice Cricetulus Cricetinae Drug Discovery medicine Animals Humans IL-2 receptor Receptor Cells Cultured Pharmacology Mice Knockout Thiadiazines Macrophages Anti-Inflammatory Agents Non-Steroidal Molecular biology Recombinant Proteins Pyridazines Interleukin 10 Cytokine medicine.anatomical_structure HEK293 Cells Knockout mouse Cytokines Female medicine.symptom Spleen |
| Zdroj: | European journal of pharmacology. 683(1-3) |
| ISSN: | 1879-0712 |
| Popis: | An orphan G-protein-coupled receptor, T cell death-associated gene 8 (TDAG8) which has been reported to be a proton sensor, inhibits the production of pro-inflammatory cytokines induced by extracellular acidification. Recently, we have found that TDAG8 knockout mice showed significant exacerbation in various immune-mediated inflammation disease models. To elucidate the role of TDAG8, we screened an in-house library to find compounds which have a profile as a TDAG8 agonist using a cyclic adenosine 5'-monophosphate assay. Among the screening hits, we focused on (3-[(2,4-dichlorobenzyl)thio]-1,6-dimethyl-5,6-dihydro-1H-pyridazino[4,5-e][1,3,4]thiadiazin-5-one) (named BTB09089). BTB09089 did not act on other proton sensing G-protein-coupled receptors such as G-protein-coupled receptor 4 (GPR4) nor ovarian cancer G-protein-coupled receptor 1 (OGR1). Moreover, BTB09089 increased cAMP level in the splenocytes from wild-type littermates but not from TDAG8-deficient mice. Thus, BTB09089 was found to be a TDAG8 specific agonist. We then investigated the effects of BTB09089 on T cells and macrophages in vitro. In splenocytes, BTB09089 suppressed the production of IL-2 stimulated with anti-CD3 and anti-CD28 antibodies. In peritoneal exuded macrophages induced by thioglycollate, BTB09089 suppressed the production of TNF-α and IL-6 while it increased that of IL-10 when stimulated with lipopolysaccharide. These effects were observed in cells from wild type mice, but not those from TDAG8 knockout mice. These results indicate that activation of TDAG8 attenuates immune-mediated inflammation by regulating the cytokine production of T cells and macrophages. |
| Databáze: | OpenAIRE |
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