Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
College of Pharmacy, The University of Findlay, Findlay, OH 45840, USA.
Biochem Biophys Res Commun. 2014 Sep 26;452(3):468-72. doi: 10.1016/j.bbrc.2014.08.089. Epub 2014 Aug 23.
Peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1) modulates phospho-signaling by catalyzing rotation of the bond between a phosphorylated serine or threonine before proline in proteins. As depletion of PIN1 increased inflammatory protein expression in cultured endothelial cells treated with bacterial endotoxin (lipopolysaccharide, LPS) and interferon-γ, we hypothesized that PIN1 knockout would increase sensitivity to LPS-induced lung inflammation in mice. Mortality due to a high dose of LPS (30mg/kg) was greater in knockout than wildtype mice. Lung myeloperoxidase activity, reflecting neutrophils, was increased to a 35% higher level in PIN1 knockout mouse lung, as compared with wildtype, after treatment with a sublethal dose of 3mgLPS/kg, ip. Unexpectedly, plasma tumor necrosis factor-α (TNF) was approximately 50% less than in wildtype mice. Knockout mice, however, were more sensitive than wildtype to TNF-induced neutrophil accumulation. The neutrophil adhesion molecule, E-selectin, was also elevated in lungs of knockout mice treated with TNF, suggesting that PIN1 depletion increases endothelial sensitivity to TNF. Indeed, TNF induced more reactive oxygen species in cultured endothelial cells depleted of PIN1 with short hairpin RNA than in control cells. Collectively, the results indicate that while PIN1 normally facilitates TNF production in LPS-treated mice, it suppresses pulmonary and endothelial reactions to the cytokine. Tissue or cell-specific effects of PIN1 may affect the overall inflammatory response to LPS and other stimuli.
肽基脯氨酰顺/反异构酶，NIMA 相互作用蛋白 1（PIN1）通过催化磷酸化丝氨酸或苏氨酸与脯氨酸之间键的旋转，调节磷酸化蛋白质中的磷酸信号。由于 PIN1 的耗竭增加了用细菌内毒素（脂多糖，LPS）和干扰素-γ处理的培养内皮细胞中炎症蛋白的表达，我们假设 PIN1 敲除会增加小鼠对 LPS 诱导的肺炎症的敏感性。用高剂量 LPS（30mg/kg）处理时，敲除型小鼠的死亡率高于野生型。与野生型相比，用亚致死剂量 3mg/kg LPS 腹腔注射后，PIN1 敲除型小鼠肺中的髓过氧化物酶活性（反映中性粒细胞）增加了 35%。出乎意料的是，血浆肿瘤坏死因子-α（TNF）水平比野生型低约 50%。然而，与野生型相比，敲除型对 TNF 诱导的中性粒细胞积聚更为敏感。TNF 处理的敲除型小鼠肺中的中性粒细胞黏附分子 E-选择素也升高，这表明 PIN1 耗竭增加了内皮细胞对 TNF 的敏感性。事实上，与对照细胞相比，用短发夹 RNA 耗尽 PIN1 的培养内皮细胞中 TNF 诱导的活性氧增加。总的来说，这些结果表明，虽然 PIN1 通常促进 LPS 处理的小鼠中 TNF 的产生，但它抑制了细胞因子对肺和内皮的反应。PIN1 的组织或细胞特异性作用可能会影响对 LPS 和其他刺激物的整体炎症反应。
