Immunosuppressive potential of astemizole against LPS activated T cell proliferation and cytokine secretion in RAW macrophages, zebrafish larvae and mouse splenocytes by modulating MAPK signaling pathway
Immunosuppressive potential of astemizole against LPS activated T cell proliferation and cytokine secretion in RAW macrophages, zebrafish larvae and mouse splenocytes by modulating MAPK signaling pathway
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DOI：
10.1016/j.intimp.2018.10.014
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发表时间：
2018-12-01
影响因子：
5.6
通讯作者：
Kang, Sun Chul
中科院分区：
文献类型：
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作者：
Jakhar, Rekha;Sharma, Chanchal;Kang, Sun Chul
本研究测定了阿司咪唑(AST)对脂多糖(LPS)诱导的巨噬细胞(体外)和斑马鱼幼体(体内)T细胞增殖和炎症反应的免疫调节作用。阿司匹林能显著抑制内毒素诱导的巨噬细胞吞噬功能(3.303+/-0.115)和溶酶体酶分泌(13.27+/-2.52)。此外，AST还可抑制斑马鱼幼体注射内毒素(0.5 mg/ml)后24 h内ROS的生成，从而抑制卵黄囊肿胀(YSE)和脊髓弯曲(SC)等形态畸形。阿司匹林还能抑制巨噬细胞产生的主要细胞因子肿瘤坏死因子-α(150.8+/-0.6)、白介素1-β(276.5+/-1.6)和前列腺素E(2)(194.6+/-0.6)pg/ml。它还抑制ROS诱导的iNOS和COX-2在斑马鱼幼体中产生的对内毒素介导的免疫功能障碍的反应。提示AST具有免疫抑制作用。此外，AST诱导的免疫抑制导致MAPK(p38、ERK和JNK)诱导的天然免疫显著下调，这与体内和体外急性炎症介质的产生减少有关。为证实其活性，用BALB/c小鼠制备脾细胞，并进行有丝分裂原激活的脾细胞增殖试验。结果提示，AST在体内外均有抑制T细胞增殖和细胞因子分泌的作用，其机制可能与干扰MAPK信号通路有关。综上所述，我们的结果显示了AST作为免疫功能障碍的对策的潜力，并建议将其作为免疫抑制化合物用于炎症性疾病。
In this study, the immunomodulatory effects of astemizole (AST) against lipopolysaccharide (LPS) mediated T cell proliferation and induction of inflammation in RAW macrophages (in vitro), and zebrafish larvae (in vivo) were determined. AST significantly suppressed the phagocytic activity of macrophages (3.303 +/- 0.115) and inhibited lysosomal enzyme secretion (13.27 +/- 2.52) induced by LPS (100 ng/ml). Moreover, AST subdued the morphological deformities such as yolk sac edema (YSE) and spinal curvature curving (SC) by inhibiting ROS generation in zebrafish larvae 24 h after microinjection of LPS (0.5 mg/ml). AST was also shown to inhibit the production of the major cytokines TNF-alpha (150.8 +/- 0.6), IL-1 beta (276.5 +/- 1.6), and PGE(2) (194.6 +/- 0.6) pg/ml in RAW macrophages. It also subdued the ROS induced iNOS and COX-2 generated in response to LPS mediated immune dysfunctions in zebrafish larvae. These results suggested the immunosuppression effect of AST. Furthermore, induction of immune-suppression due to AST resulted in significant down-regulation of innate immunity directed by MAPK (p38, ERK and JNK), which was found to be associated with decreased production of acute inflammatory mediators both in vitro and in vivo. To confirm its activity, splenocytes were prepared using BALB/c mice and a mitogen activated splenocyte proliferation assay was also performed. Our findings suggest that AST has the ability to inhibit T cell proliferation and cytokine secretion both in vitro and in vivo by interfering with MAPK signaling pathway. Taken together, our results showed the potential of AST as a countermeasure to immune dysfunction and suggest its use as immunosuppressant compound in inflammatory disease.