Antagonist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice
Antagonist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice
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DOI：
10.1002/art.21745
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发表时间：
2006-04-01
影响因子：
--
通讯作者：
Yasukawa, M
中科院分区：
文献类型：
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作者：
Hasegawa, H;Inoue, A;Yasukawa, M
客观的。唾液腺的单核细胞浸润是干燥综合征（SS）及其动物模型的主要特征。趋化因子的局部产生和浸润细胞上趋化因子受体的存在可能参与了这一过程。本研究旨在探讨MRL/lpr小鼠自身免疫性唾液腺炎发生过程中趋化因子的表达以及趋化因子拮抗剂对唾液腺炎的治疗作用。方法。将NH2末端截短的干扰素诱导蛋白10（IP-10）/CXCL10类似物转染至非转移性成纤维细胞系MRL/N-1中，并皮下注射至MRL/lpr小鼠中，并监测对唾液腺炎的影响。结果。 N-末端被5个或更多氨基酸残基截短的IP-10类似物未能诱导CXCR3表达细胞的趋化性和钙流入。其中，最有效的拮抗剂 (AT) (IP-10-AT) 是去除 5 个 N 末端氨基酸残基后添加蛋氨酸的分子。唾液腺中产生的干扰素-γ诱导导管上皮中 Th1 相关趋化因子 IP-10、由干扰素-γ/CXCL9 诱导的单因子和干扰素诱导型 T 细胞趋化因子/CXCL11 的表达显着增加，而 Th2 相关趋化因子胸腺和激活调节趋化因子 (TARC)/ 的表达显着增加。在唾液腺炎期间几乎检测不到 CCL17 和单核细胞来源的趋化因子/CCL22。与对照和携带 TARC-AT 的小鼠相比，在唾液腺炎早期将 IP-10-AT 接种到 MRL/lpr 小鼠中，显着减少了导管周围单核细胞浸润和实质破坏。这是由于 CXCR3+ T 细胞（主要是 Th1 细胞）浸润显着减少，导致干扰素 γ 产生减少。结论。我们制备了一种新型强效 IP-10 拮抗剂，并证明其能够改善自身免疫性唾液腺炎的进展。该药物可能为 SS 提供新的治疗方法。
Objective. Mononuclear cell infiltration of the salivary glands is a major feature of Sjogren's syndrome (SS) and its animal model. Local generation of chemokines and the presence of chemokine receptors on the infiltrating cells may be involved in this process. We undertook the present study to investigate the expression of chemokines during the development of autoimmune sialadenitis in MRL/lpr mice and the therapeutic effect of chemokine antagonists on sialadenitis.Methods. NH2-terminal-truncated interferon-inducible protein 10 (IP-10)/CXCL10 analogs were transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, and injected subcutaneously into MRL/lpr mice, and the effects on sialadenitis were monitored.Results. IP-10 analogs truncated by 5 or more amino acid residues from the N-terminal failed to induce chemotaxis and calcium influx by CXCR3-expressing cells. Of these, the most potent antagonist (AT) (IP-10-AT) was a molecule with methionine added after removal of the 5 N-terminal amino acid residues. Significantly increased expression of the Th1-associated chemokines IP-10, monokine induced by interferon-gamma/ CXCL9, and interferon-inducible T cell chemo-attractant/CXCL11 was induced in the ductal epithelium by interferon-gamma produced in the salivary glands, whereas expression of the Th2-associated chemokines thymus and activation-regulated chemokine (TARC)/ CCL17 and monocyte-derived chemokine/CCL22 was almost undetectable during sialadenitis. Inoculation of IP-10-AT into MRL/lpr mice during the early stage of sialadenitis significantly reduced periductal mononuclear cell infiltration and parenchymal destruction compared with these features in control and TARC-AT-bearing mice. This was due to a significant reduction in infiltration of CXCR3+ T cells, predominantly Th1 cells, resulting in decreased interferon-gamma production.Conclusion. We prepared a novel potent IP-10 antagonist and demonstrated its ability to ameliorate the progression of autoimmune sialadenitis. This agent may provide a new therapeutic approach to SS.