CXCL10 blockade protects mice from cyclophosphamide-induced cystitis.
CXCL10 blockade protects mice from cyclophosphamide-induced cystitis.
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DOI：
10.1186/1476-8518-6-6
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发表时间：
2008-10-28
期刊：
影响因子：
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通讯作者：
Lillard, James W Jr
中科院分区：
文献类型：
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作者：
Sakthivel, Senthilkumar K;Singh, Udai P;Lillard, James W Jr
背景技术背景：在间质性膀胱炎（IC）患者中检查了血清CXCR 3配体水平的变化;在环磷酰胺（CYP）诱导的小鼠急性膀胱炎期间，血清以及外周和局部白细胞亚群表达的CXCR 3、CXCR 3配体和细胞因子的表达模式相似。结果：γ-干扰素诱导的血清单核细胞因子水平（IFN-γ）在IC患者中，IFN-γ诱导蛋白-10（IP-10/CXCL 10）和IFN-γ诱导T细胞α趋化因子（I-TAC/CXCL 11）升高。这些临床特征与CYP诱导的小鼠膀胱炎密切相关。这些CXCR 3配体和局部辅助性T细胞1型（Th 1）细胞因子的血清水平也增加。我们证明，CXCR 3以及CXCL 9，CXCL 10和CXCL 11 mRNA的膀胱淋巴细胞显着表达，而CXCR 3和CXCL 9转录显着表达的髂淋巴结白细胞后，顺铂治疗。我们还发现，在CYP诱导的小鼠膀胱炎后，全身（脾脏）和粘膜（膀胱和髂淋巴结）部位的CD 4 + T细胞、肥大细胞、自然杀伤（NK）细胞和NKT细胞数量增加。重要的是，CXCL 10的封锁衰减这些增加引起的膀胱炎。结论：抗体（Ab）介导的抑制最丰富的血清CXCR 3配体，CXCL 10，在小鼠中减少CXCR 3配体的局部生产以及Th 1细胞因子表达的局部白细胞，并降低相应的血清水平，以减少CYP诱导的膀胱炎的严重程度。本研究是第一个证明膀胱炎中趋化因子的一些细胞和分子机制的研究，并可能代表这种疾病的新药物靶点。
BACKGROUND: Alterations in serum CXCR3 ligand levels were examined in interstitial cystitis (IC) patients; similar expression patterns in serum as well as CXCR3, CXCR3 ligands, and cytokines expressed by peripheral and local leukocyte subpopulations were characterized during cyclophosphamide (CYP)-induced acute cystitis in mice.RESULTS: Serum levels of monokine-induced by interferon-gamma (IFN-gamma) (MIG/CXCL9), IFN-gamma-inducible protein-10 (IP-10/CXCL10), and IFN-gamma-inducible T cell alpha chemoattractant (I-TAC/CXCL11) were elevated in patients with IC. These clinical features closely correlated with CYP-induced cystitis in mice. Serum levels of these CXCR3 ligands and local T helper type 1 (Th1) cytokines were also increased. We demonstrate that CXCR3 as well as CXCL9, CXCL10 and CXCL11 mRNA were significantly expressed by urinary bladder lymphocytes, while CXCR3 and CXCL9 transcripts were significantly expressed by iliac lymph node leukocytes following CYP treatment. We also show that the number of CD4+ T cells, mast cells, natural killer (NK) cells, and NKT cells were increased at systemic (spleen) and mucosal (urinary bladder and iliac lymph nodes) sites, following CYP-induced cystitis in mice. Importantly, CXCL10 blockade attenuated these increases caused by CYP.CONCLUSION: Antibody (Ab)-mediated inhibition of the most abundant serum CXCR3 ligand, CXCL10, in mice decreased the local production of CXCR3 ligands as well as Th1 cytokines expressed by local leukocytes, and lowered corresponding serum levels to reduce the severity of CYP-induced cystitis. The present study is among the first to demonstrate some of the cellular and molecular mechanisms of chemokines in cystitis and may represent new drug target for this disease.