Protein inhibitor of activated STAT3 (PIAS3) attenuates psoriasis and associated inflammation

Abstract

AbstractPsoriasis is a common chronic inflammatory multisystem disease accompanied by hyperproliferation and inflammation of epidermal keratinocytes. Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and plays an important role in epidermal keratinocytes of human psoriatic skin lesions. In this study, we investigated the effects of an endogenous STAT3 inhibitor, a protein inhibitor of activated STAT3 (PIAS3), on the proliferation and inflammation of psoriatic cells. The expression of PIAS3 in psoriatic tissues and healthy skin was analyzed using the Gene Expression Omnibus database and clinical samples. The human immortalized epidermal (HaCaT) cells were used to establish an in vitro psoriasis‐like cell model. 3–(4,5–dimethylthiazol–2–yl)–5–(3–carboxymethoxyphenyl)–2–(4–sulfophenyl)–2H–thethrazolium (MTS) assay was used to detect cell proliferation. Flow cytometry was used to determine apoptosis levels. Real‐time PCR, western blotting, and enzyme‐linked immunosorbent assay (ELISA) were used to detect the expression levels of related factors. Furthermore, a mouse model of imiquimod (IMQ)‐induced psoriatic dermatitis was established to verify the in vitro experimental results. The results showed that the mRNA and protein expression levels of PIAS3 were lower in psoriatic lesions than in normal tissues. PIAS3 inhibited the proliferation and promoted apoptosis of M5‐induced HaCaT cells. Simultaneously, the mRNA and protein expression levels of tumor necrosis factor–alpha (TNF‐α), interleukin–6 (IL‐6), interleukin–8 (IL‐8), and keratin 17 (K17) were significantly decreased and that of p53 was increased, thereby inhibiting the inflammatory response and promoting apoptosis. PIAS3 inhibited the transcription activity of STAT3 and noncanonical nuclear factor‐kappaB (NF‐κB). Furthermore, PIAS3 attenuated IMQ‐induced psoriasis‐like inflammation in mice. Our findings suggest that PIAS3 plays an important role in psoriasis by regulating the STAT3/NF‐κB signaling pathway and p53. The lack of PIAS3 may represent a novel mechanism underlying the pathogenesis of psoriasis.