Stat3 as a Therapeutic Target for the Treatment of Psoriasis: A Clinical Feasibility Study with STA-21, a Stat3 Inhibitor
Ken Miyoshi1,5, Mikiro Takaishi1,5, Kimiko Nakajima1, Mitsunori Ikeda1, Takashi Kanda1, Masahito Tarutani1, Tatsuo Iiyama2, Naoki Asao3, John DiGiovanni4 and Shigetoshi Sano1
Epidermal keratinocytes in psoriatic lesions are characterized by activatedStat3, and increased levels of cytokines and growth factors that promote Stat3 activation have been found within psoriatic lesions. K5.Stat3C transgenic mice, in which keratinocytes express a constitutively active Stat3, develop psoriasis-like skin lesions. In this study, we examined whether STA-21, a small Stat3 inhibitor, could be useful in ameliorating the skin lesions not only in the model mousebut also in human psoriasis. Treatment with STA-21 markedly inhibited the cytokine-dependent nuclear translocation of Stat3 in normal human keratinocytes in vitro. Keratinocyte proliferation was inhibited by STA-21 in a dose-dependent manner through downregulation of c-Myc and cyclin D1, whereas involucrin, transglutaminase 1, and keratin 10 levels were upregulated. Topical application of STA-21abolished the generation of skin lesions in K5.Stat3C mice. Finally, we treated psoriasis patients with STA21-containing ointment in a nonrandomized study. Psoriatic lesions in six of the eight patients showed improvement after topical STA-21 treatment for 2 weeks. Therefore, we conclude that targeting Stat3 may lead to a therapy for psoriasis.
Journal of Investigative Dermatology (2011) 131,108–117; doi:10.1038/jid.2010.255; published online 2 September 2010
INTRODUCTION Our previous study elucidated the role of Stat3 signaling in keratinocytes during the development of psoriatic lesions (Sano et al., 2005a, 2008). K5.Stat3C transgenic mice, in which Stat3 is constitutively active in keratinocytes, develop psoriasiform lesions after wounding stimuli or topical treatment with the tumorpromoter 12-O-tetradecanoylphorbol-13-acetate (TPA), which strongly suggests that Stat3 activation is required for the development of psoriasis. Previous studies have shown that the IL-23/IL-17 pathway is linked to the induction of a number of inflammatory diseases, including multiple sclerosis, arthritis, inflammatory bowel diseases, and psoriasis (Cua et al., 2003; Murphy et al.,
1Department of Dermatology, Kochi Medical School, Kochi University, Okocho, Nankoku, Japan; 2Clinical Trial Center, Kochi Medical School, Kochi University, Okocho, Nankoku, Japan; 3Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, Japan and 4 Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, Texas, USA
Theseauthors contributed equally to this work.
Correspondence: Shigetoshi Sano, Department of Dermatology, Kochi Medical School, Kochi University, Kohasu, Okocho, Nankoku 783-8505, Japan. E-mail: firstname.lastname@example.org Abbreviations: HB-EGF, heparin-binding EGF-like growth factor; NHK, normal human keratinocyte; TPA, 12-O-tetradecanoylphorbol-13-acetate Received 15 January 2010; revised 22 June2010; accepted 1 July 2010; published online 2 September 2010
2003; Yen et al., 2006; Wilson et al., 2007). The most distinct evidence for the role of IL-23/Th17 in psoriasis comes from clinical studies. A clinical study showed that anti-IL-12/ IL-23p40 therapy is an effective treatment for psoriasis (Krueger et al., 2007). Amelioration of psoriasis is associated with reduced Th17 responses (Zabaet al., 2007; Haider et al., 2008). IL-22, a cytokine produced from Th17, is elevated in the blood of psoriasis patients (Wolk et al., 2006), and triggering the IL-22R mediates the proliferation and migration of keratinocytes via Stat3 activation (Boniface et al., 2005). Furthermore, studies using gene-targeted mice and reconstituted human epidermis revealed that IL-22 mediates acanthosis...