Tetomilast Suppressed Production of Proinflammatory Cytokines from Human Monocytes and Ameliorated Chronic Colitis in IL-10-Deficient Mice
Tetomilast Suppressed Production of Proinflammatory Cytokines from Human Monocytes and Ameliorated Chronic Colitis in IL-10-Deficient Mice
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DOI：
10.1002/ibd.20524
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发表时间：
2008-11-01
影响因子：
4.9
通讯作者：
Hibi, Toshifumi
中科院分区：
文献类型：
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作者：
Ichikawa, Hitoshi;Okamoto, Susumu;Hibi, Toshifumi
背景：替托司特（OPC-6535）最初是作为一种抑制中性粒细胞产生超氧化物的化合物开发的。虽然其作用机制尚未完全了解，但已假定磷酸二酯酶4型抑制功能。已报道了PDE 4抑制剂对慢性炎症性疾病如慢性阻塞性肺病的治疗作用。在这项研究中，我们的目的是研究是否替托司特可能是一种新的药物，炎症性肠病，进一步阐明其cytokine effects.Methods：从人外周血单个核细胞的细胞因子测定酶联免疫吸附试验（ELISA）和细胞因子微球阵列。通过逆转录聚合酶链反应（RT-PCR）定量转录物。转录因子的磷酸化用荧光定量法检测。为了检查其在体内的作用，每日一次口服剂量的替托司特在小鼠IL-10（-/-）慢性colis.Results：替托司特抑制TNF-α和IL-12，但不从脂多糖（LPS）刺激的人单核细胞IL-10的生产进行了测试。它抑制来自CD 4淋巴细胞的TNF-α、IFN-γ和IL-10。替托司特在转录水平抑制细胞因子的产生，但不改变p65、ERK、p38和STAT 3的磷酸化。蛋白激酶A抑制剂HT-89不能阻断替托司特的作用，提示其不依赖于经典的cAMP/PKA通路。IL-10对于替托司特对TNF-α和IL-12的抑制作用不是必需的。替托司特可改善IL-10（-/-）慢性结肠炎，降低临床症状、血清淀粉样蛋白A和组织学评分，降低TNF-α mRNA表达。结合体内数据，这些发现支持替托司特作为炎症性肠病新药的可行性。
Background: Tetomilast (OPC-6535) was originally developed as a Compound inhibiting superoxide production in neutrophils. Although its mechanism of action is not completely understood, phosphodiesterase type 4 inhibitory function has been postulated. The therapeutic effect of PDE4 inhibitors has been reported for chronic inflammatory disorders such as chronic obstructive pulmonary diseases. In this study we aimed to examine whether tetomilast could be a novel drug for inflammatory bowel diseases by further clarifying its antiinflammatory effects.Methods: Cytokines from human peripheral blood mononuclear cells were measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Beads Array. The transcripts were quantified by reverse-transcriptase polymerase chain reaction (RT-PCR). Phosphorylation of transcription factors was examined by phosflow. To examine its in vivo effect, a once-daily oral dose of tetomilast was tested in murine IL-10(-/-) chronic colitis.Results: Tetomilast suppressed TNF-alpha and IL-12 but not IL-10 production from lipopolysaccharide (LPS)-stimulated human monocytes. It suppressed TNF-a, IFN-gamma, and IL-10 from CD4 lymphocytes. Tetomilast suppressed cytokine production at the transcriptional level but did not alter phosphorylation of p65, ERK, p38, and STAT3. HT-89, a protein kinase A inhibitor, did not abolish the effect of tetomilast, suggesting that it was independent from the classical cAMP/PKA pathway. IL-10 was not essential to the inhibitory effect of tetomilast on TNF-alpha and IL-12. Tetomilast ameliorated IL-10(-/-) chronic colitis with reduced clinical symptoms, serum amyloid A, and histological scores with decreased TNF-alpha mRNA expression.Conclusions: Tetomilast exerts its antiinflammatory effects on human monocytes and CD4 cells. Combined with in vivo data these findings support the feasibility of tetomilast as a novel drug for inflammatory bowel diseases.