期刊
ANNALS OF THE RHEUMATIC DISEASES
卷 74, 期 5, 页码 936-943出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/annrheumdis-2013-204256
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资金
- Deutsche Forschungsgesellschaft [DI 1537/4-1, DI 1537/5-1, DI 1537/7-1, BE 5191/1-1, AK 144/1-1, SCHE 1583/7-1]
- IZKF in Erlangen [A40, J29]
- ELAN-Program of the University of Erlangen-Nuremberg
- Medicine of the Ernst Jung Foundation
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.
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