野生型p53诱导的磷酸酶1（Wip1）被认为是当前癌症治疗中有希望的药物靶点。最近的研究也表明，Wip1的缺失会显著地促进中性粒细胞炎症反应。Wip1是否参与炎症性肠病的调控尚不清楚。在本研究中，我们发现Wip基因敲除（KO）小鼠比野生型小鼠更容易感染由硫酸葡聚糖钠（DSS）诱发的结肠炎：Wip1KO小鼠被证实存活率更低、体重下降更快、疾病活动指数上升，具有更短的结肠长度以及更严重的结肠病理特征。
在骨髓嵌合体小鼠模型中，我们证实了Wip1可控制体内免疫细胞的炎症反应。IL-17的缺失（Wip1/IL-17双基因敲除小鼠）显著地减轻Wip1基因敲除小鼠的病理。经过DSS处理过的野生型和Wip1基因敲除小鼠的中性粒细胞会表达极高的IL-17。将Wip1KO（WipKO组）或者双基因敲除小鼠（双基因敲除组）的中性粒细胞转移到IL-17KO小鼠后，双基因敲除组比WipKO组更能抵抗DSS-诱导的结肠炎。
这些数据共同表明，Wip1通过调节免疫细胞，进而调节机体对结肠炎的敏感性。Wip1KO小鼠中性粒细胞中IL-17表达的增强有助于提高结肠炎的敏感度及严重性。因此，Wip1可能被作为结肠炎治疗的药物靶点。
PhosphataseWip1MastersIL-17-producingNeutrophil-mediatedColitisinMice
HuX1,WangP,DuJetal.
1StateKeyLaboratoryofMembraneBiology,ChineseAcademyofSciences,China.
ABSTRACT
Wild-typep53-inducedphosphatase1(Wip1)iscurrentlybelievedtobeapromisingdrugtargetforcancertherapy.OurrecentstudiesshowedthatdeletionofWip1remarkablypromotedneutrophilinflammatoryresponse.WhetherWip1isinvolvedintheregulationofinflammatoryboweldiseaseisunknown.Inthepresentstudy,wefoundthatWip1knockout(KO)miceweremoresusceptibletocolitisinducedbydextransulphatesodium(DSS)thanwild-typemiceassubstantiatedbythelowermousesurvivalratio,rapidbodyweightloss,increaseddiseaseactivityindex,shortercolonlength,andmoreseverepathologyofcolonsinWip1KOmice.Usingfullbonemarrowchimeramousemodels,wedemonstratedthatWip1intrinsicallycontrolsinflammatoryresponseofimmunecells.DeletionofIL-17(Wip1/IL-17doubleKOmice)significantlyrescuedthepathologyinWip1KOmice.NeutrophilsofDSS-treatedwild-typeandWip1KOmiceexpressedsignificantlyhigherIL-17.AfteradoptivetransferofsortedWip1KOordoubleKOneutrophilsintoIL-17KOmice,micereceivingdoubleKOneutrophilsweremoreresistanttoDSS-inducedcolitisthanmicereceivingWip1KOneutrophils.ThesedatacollectivelyindicatethatWip1modulateshostsensitivitytocolitisbyintrinsicallyregulatingimmunecells.TheenhancedIL-17expressioninneutrophilscontributedtotheincreasedsensitivityandseverityofcolitisinWip1KOmice.Thus,Wip1maybeusedasadrugtargettotreatcolitis.
原文来源：InflammBowelDis.Mar4
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