Inhibition of casein kinase II reduces TGFβ induced fibroblast activation and ameliorates experimental fibrosis
Inhibition of casein kinase II reduces TGFβ induced fibroblast activation and ameliorates experimental fibrosis
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DOI：
10.1136/annrheumdis-2013-204256
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发表时间：
2015-05-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Zhang, Yun;Dees, Clara;Distler, Joerg H. W.
目的酪蛋白激酶II(Casein Kinase II，CK2)是一种具有结构性活性的丝氨酸/苏氨酸蛋白激酶，在细胞转化和肿瘤发生中起关键作用。本研究的目的是探讨CK2是否参与系统性硬皮病患者成纤维细胞的病理性激活，并评价CK2抑制剂的抗纤维化作用。方法采用免疫组织化学方法检测CK2、JAK2和STAT3在人皮肤和实验性纤维化中的激活情况。选择性CK2抑制剂4，5，6，7-四溴苯并三唑(TBB)可抑制CK2信号转导。采用博莱霉素诱导的小鼠皮肤纤维化模型和转化生长因子β受体I(TBR)诱导的小鼠皮肤纤维化模型，评价特异性CK2抑制的体内抗纤维化作用。TBB对CK2的抑制可阻断转化生长因子β诱导的JAK2/STAT3信号通路的激活，并阻止转化生长因子β对成纤维细胞胶原释放和肌成纤维细胞分化的刺激作用。抑制CK2可通过减少真皮增厚、减少肌成纤维细胞计数和减少胶原的积累来预防博莱霉素诱导的和TBR诱导的皮肤纤维化。使用TBB治疗也可使预先形成的纤维化消退。TBB的抗纤维化作用与体内JAK2/STAT3信号的激活减少有关。结论CK2在SSC中被激活，并通过调节JAK2/STAT3信号参与成纤维细胞的激活。抑制CK2可减少转化生长因子β的促纤维化作用，抑制实验性纤维化。因此，靶向CK2可能是治疗SSc和其他纤维化疾病的一种新方法。
Objectives Casein kinase II (CK2) is a constitutively active serine/threonine protein kinase that plays a key role in cellular transformation and tumorigenesis. The purpose of the study was to characterise whether CK2 contributes to the pathologic activation of fibroblasts in patients with SSc and to evaluate the antifibrotic potential of CK2 inhibition.Methods Activation of CK2, JAK2 and STAT3 in human skin and in experimental fibrosis was analysed by immunohistochemistry. CK2 signalling was inhibited by the selective CK2 inhibitor 4, 5, 6, 7-Tetrabromobenzotriazole (TBB). The mouse models of bleomycin-induced and TGF beta receptor I (TBR)-induced dermal fibrosis were used to evaluate the antifibrotic potential of specific CK2 inhibition in vivo.Result Increased expression of CK2 was detected in skin fibroblasts of SSc patients. Inhibition of CK2 by TBB abrogated the TGF beta-induced activation of JAK2/STAT3 signalling and prevented the stimulatory effects of TGF beta on collagen release and myofibroblasts differentiation in cultured fibroblasts. Inhibition of CK2 prevented bleomycin-induced and TBR-induced skin fibrosis with decreased dermal thickening, lower myofibroblast counts and reduced accumulation of collagen. Treatment with TBB also induced regression of pre-established fibrosis. The antifibrotic effects of TBB were accompanied by reduced activation of JAK2/STAT3 signalling in vivo.Conclusions We provide evidence that CK2 is activated in SSc and contributes to fibroblast activation by regulating JAK2/STAT3 signalling. Inhibition of CK2 reduced the profibrotic effects of TGF beta and inhibited experimental fibrosis. Targeting of CK2 may thus be a novel therapeutic approach for SSc and other fibrotic diseases.