Inhibition of casein kinase II reduces TGF? induced fibroblast activation and ameliorates experimental fibrosis

Zhang Y, Dees C, Beyer C, Lin NY, Distler A, Zerr P, Palumbo K, Susok L, Kreuter A, Distler O, Schen G, Distler J (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 74

Pages Range: 936-43

Journal Issue: 5

DOI: 10.1136/annrheumdis-2013-204256

Abstract

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 TGF? 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 TGF?-induced activation of JAK2/STAT3 signalling and prevented the stimulatory effects of TGF? 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 TGF? and inhibited experimental fibrosis. Targeting of CK2 may thus be a novel therapeutic approach for SSc and other fibrotic diseases.

Authors with CRIS profile

Involved external institutions

Ruhr-Universität Bochum (RUB) Germany (DE) HELIOS Kliniken Germany (DE) Universitätsspital Zürich (USZ) Switzerland (CH)

How to cite

APA:

Zhang, Y., Dees, C., Beyer, C., Lin, N.-Y., Distler, A., Zerr, P.,... Distler, J. (2015). Inhibition of casein kinase II reduces TGF? induced fibroblast activation and ameliorates experimental fibrosis. Annals of the Rheumatic Diseases, 74(5), 936-43. https://doi.org/10.1136/annrheumdis-2013-204256

MLA:

Zhang, Yun, et al. "Inhibition of casein kinase II reduces TGF? induced fibroblast activation and ameliorates experimental fibrosis." Annals of the Rheumatic Diseases 74.5 (2015): 936-43.

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