A therapeutic strategy for psoriasis: STAT3 and NF-κB inhibition by tussilagonone as an Nrf2 activator in keratinocytes

Psoriasis is a common inflammatory skin disorder with a prevalence of 2 – 3% in the world's population. It is characterized by abnormal keratinocyte hyperproliferation, resulting in thickening of the epidermis and stratum corneum [1]. In the present study, we investigated pharmacological effects of tussilagonone (TGN), a sesquiterpenoid isolated from Tussilago farfara, on the transcription factors related to pathogenesis of psoriasis. TGN upregulated the ARE-luciferase activity time- and dose-dependently (up to 19.1-fold and 17.7-fold, respectively). Also, it induced the protein expression of Nrf2 and its downstream target, heme oxygenase-1 (HO-1) in HaCaT cells. In addition, TGN treatment increased the nuclear translocation of Nrf2, suggesting that TGN activates Nrf2 pathway. To elucidate whether TGN could reduce the activation of STAT3 and NF-κB, crucial transcription factors involved in the pathogenesis of psoriasis, we conducted western blot analysis and luciferase assay. TGN inhibited IL-6-induced STAT3 phosphorylation and STAT3-dependent transcriptional luciferase activity, and also suppressed TNF-α-induced NF-κB activation. Knockdown of Nrf2 or HO-1 by small interfering RNA (siRNA) abrogated inhibitory effects of TGN on STAT3 and NF-κB activation, indicating that Nrf2 upregulation by TGN can regulate STAT3 and NF-κB pathway in keratinocytes. Moreover, proliferation assay revealed that 10µM TGN treatment inhibited IL-6-induced HaCaT cell proliferation and the protein expression of keratin 16, one of the markers for hyperproliferation. Taken together, these results suggest that TGN, as an effective Nrf2 activator which plays an important role in regulating STAT3 and NF-κB activation, can be a promising therapeutic candidate for treatment psoriasis.

[1] Alice B. Gottlieb. Nat Rev Drug Discov 2005; 4: 19 – 34