A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development
A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development
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DOI：
10.4049/jimmunol.173.4.2280
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发表时间：
2004-08-15
影响因子：
4.4
通讯作者：
Adorini, L
中科院分区：
文献类型：
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作者：
Giarratana, N;Penna, G;Adorini, L
1型糖尿病（T1 D）是一种自身免疫性疾病，其特征是白细胞浸润到胰岛中，我们以前已经证明，用维生素D类似物治疗成年NOD小鼠可以阻止胰岛炎的进展，阻断Th 1细胞浸润到胰腺中，并显着减少T1 D的发展，表明胰岛细胞抑制趋化因子的产生。在这项研究中，我们表明，所有的TLRs表达的小鼠和人类胰岛细胞，其参与病原体衍生的配体显着增强促炎趋化因子的生产。维生素D类似物显著下调胰岛细胞的体外和体内促炎趋化因子的产生，抑制T细胞募集到胰岛和T1 D发展。体内胰岛趋化因子产生的抑制在TLR配体再刺激后持续存在，并与NF-κ B抑制剂IkappaBa转录的上调和NF-κ Bp 65核转位的阻滞相关，突出了维生素D受体配体发挥的新作用机制，可能与T1 D和其他自身免疫性疾病的治疗相关。
Type 1 diabetes (T1D) is an autoimmune disease characterized by leukocyte infiltration into the pancreatic islets, and we have previously shown that treatment of adult NOD mice with a vitamin D analog arrests the progression of insulitis, blocks Th1 cell infiltration into the pancreas, and markedly reduces T1D development, suggesting inhibition of chemokine production by islet cells. In this study, we show that all TLRs are expressed by mouse and human islet cells, and their engagement by pathogenderived ligands markedly enhances proinflammatory chemokine production. The vitamin D analog significantly down-regulates in vitro and in vivo proinflammatory chemokine production by islet cells, inhibiting T cell recruitment into the pancreatic islets and T1D development. The inhibition of islet chemokine production in vivo persists after restimulation with TLR ligands and is associated with up-regulation of IkappaBa transcription, an inhibitor of NF-kappaB and with arrest of NF-kappaBp65 nuclear translocation, highlighting a novel mechanism of action exerted by vitamin D receptor ligands potentially relevant for the treatment of T1D and other autoimmune diseases.