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Extended Report
Inhibition of casein kinase II reduces TGFβ induced fibroblast activation and ameliorates experimental fibrosis
  1. Yun Zhang1,
  2. Clara Dees1,
  3. Christian Beyer1,
  4. Neng-Yu Lin1,
  5. Alfiya Distler1,
  6. Pawel Zerr1,
  7. Katrin Palumbo1,
  8. Laura Susok2,
  9. Alexander Kreuter3,
  10. Oliver Distler4,
  11. Georg Schett1,
  12. Jörg H W Distler1
  1. 1Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Dermatology, Ruhr-University Bochum, Bochum, Germany
  3. 3Department of Dermatology, Venereology, and Allergology, HELIOS St. Elisabeth Hospital Oberhausen, Germany
  4. 4Rheumaklinik, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Dr Jörg Distler, Department of Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen D-91054, Germany; Joerg.distler{at}uk-erlangen.de

Abstract

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 TGFβ 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 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.

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 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.

  • Fibroblasts
  • Systemic Sclerosis
  • Treatment

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