Prostasin attenuates inducible nitric oxide synthase expression in lipopolysaccharide-induced urinary bladder inflammation
Prostasin attenuates inducible nitric oxide synthase expression in lipopolysaccharide-induced urinary bladder inflammation
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DOI：
10.1152/ajprenal.00047.2006
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发表时间：
2006-09-01
影响因子：
4.2
通讯作者：
Chai, Karl X.
中科院分区：
文献类型：
--
作者：
Chen, Li-Mei;Wang, Cindy;Chai, Karl X.
前列腺素是一种糖基磷脂酰肌醇锚定的丝氨酸蛋白酶，具有上皮钠通道激活和肿瘤侵袭抑制活性。我们确定膀胱是前列腺素的表达位点。在小鼠中，通过逆转录和实时聚合酶链反应检测小鼠膀胱中前列腺素mRNA的表达，并通过免疫组织化学在尿路上皮细胞中定位前列腺素蛋白。在腹腔注射细菌脂多糖（LPS）的小鼠中，膀胱前列腺素mRNA表达下调，而诱导型一氧化氮合酶（iNOS）、环氧合酶-2（COX-2）、干扰素-γ（IFNγ）、TNF-α、IL-1α和IL-6的表达上调。转基因小鼠膀胱中病毒启动子驱动的人类前列腺素同源物的表达减弱了LPS对iNOS的诱导，但并没有消除这种诱导。然而，LPS 对 COX-2、TNF-α、IL-1 α 和 IL-6 表达的诱导并未因前列腺素转基因表达而减弱。脂质体介导的前列腺素表达质粒递送至小鼠膀胱对 LPS 诱导的 iNOS 表达产生类似的减弱作用，同时不影响 COX-2 或细胞因子的诱导。接受表达催化突变体前列腺素的质粒的小鼠没有表现出iNOS诱导减弱表型。我们提出了前列腺素的蛋白水解机制，以在 LPS 诱导的膀胱炎症期间拦截细胞因子信号传导。
Prostasin is a glycosylphosphatidylinositol- anchored serine protease, with epithelial sodium channel activation and tumor invasion suppression activities. We identified the bladder as an expression site of prostasin. In the mouse, prostasin mRNA expression was detected by reverse transcription and real-time polymerase chain reaction in the bladder, and the prostasin protein was localized by immunohistochemistry in the urothelial cells. In mice injected intraperitoneally with bacterial lipopolysaccharide (LPS), bladder prostasin mRNA expression was downregulated, whereas the expression of inducible nitric oxide synthase ( iNOS), cyclooxygenase-2 (COX-2), interferon-gamma (IFN gamma), TNF-alpha, IL-1 alpha, and IL-6 was upregulated. Viral promoter-driven expression of the human prostasin homolog in the bladder of transgenic mice attenuated the LPS induction of iNOS but did not abolish the induction. LPS induction of COX-2, TNF-alpha, IL-1 alpha, and IL-6 expression, however, was not reduced by prostasin transgene expression. Liposome-mediated delivery of prostasin-expressing plasmid into mouse bladder produced similar attenuation effects on LPS-induced iNOS expression, while not affecting COX-2 or cytokine induction. Mice receiving plasmid expressing a catalytic mutant prostasin did not manifest the iNOS induction attenuation phenotype. We propose a proteolytic mechanism for prostasin to intercept cytokine signaling during LPS-induced bladder inflammation.