Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Department of Dermatology, Ruhr-University Bochum, Bochum, Germany.
Ann Rheum Dis. 2015 May;74(5):936-43. doi: 10.1136/annrheumdis-2013-204256. Epub 2014 Jan 15.
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.
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 TGFβ receptor I (TBR)-induced dermal fibrosis were used to evaluate the antifibrotic potential of specific CK2 inhibition in vivo.
Increased expression of CK2 was detected in skin fibroblasts of SSc patients. Inhibition of CK2 by TBB abrogated the TGFβ-induced activation of JAK2/STAT3 signalling and prevented the stimulatory effects of TGFβ 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.
We provide evidence that CK2 is activated in SSc and contributes to fibroblast activation by regulating JAK2/STAT3 signalling. Inhibition of CK2 reduced the pro-fibrotic effects of TGFβ and inhibited experimental fibrosis. Targeting of CK2 may thus be a novel therapeutic approach for SSc and other fibrotic diseases.
酪蛋白激酶 2（CK2）是一种组成性激活的丝氨酸/苏氨酸蛋白激酶，在细胞转化和肿瘤发生中起关键作用。本研究旨在探讨 CK2 是否有助于 SSc 患者成纤维细胞的病理性激活，并评估 CK2 抑制的抗纤维化潜力。
通过免疫组织化学分析人皮肤和实验性纤维化中 CK2、JAK2 和 STAT3 的激活。通过选择性 CK2 抑制剂 4,5,6,7-四溴苯并三唑（TBB）抑制 CK2 信号转导。使用博来霉素诱导和 TGFβ 受体 I（TBR）诱导的皮肤纤维化小鼠模型，评估特异性 CK2 抑制在体内的抗纤维化潜力。
在 SSc 患者的皮肤成纤维细胞中检测到 CK2 表达增加。TBB 抑制 CK2 可阻断 TGFβ 诱导的 JAK2/STAT3 信号转导的激活，并防止 TGFβ 对培养成纤维细胞中胶原释放和肌成纤维细胞分化的刺激作用。CK2 抑制可预防博来霉素诱导和 TBR 诱导的皮肤纤维化，减少真皮增厚、肌成纤维细胞计数降低和胶原积累。TBB 治疗还可诱导已建立的纤维化消退。TBB 的抗纤维化作用伴有体内 JAK2/STAT3 信号转导的激活减少。
我们提供的证据表明，CK2 在 SSc 中被激活，并通过调节 JAK2/STAT3 信号转导促进成纤维细胞激活。CK2 抑制可减少 TGFβ 的促纤维化作用并抑制实验性纤维化。因此，靶向 CK2 可能是 SSc 和其他纤维化疾病的一种新的治疗方法。
