Analyses of the patho mechanism of Stat3 activation a crosstalk between epidermal and immunocytes require for the development of psonriasis

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We have previously demonstrated that psoriatic epidermis was characterized by Stat3 activation, which was necessary for the development of psoriatic lesion in a transgenic mouse model. Also, a crosstalk between epidermal keratinocytes and T cells was required for it In the presnt project, we investigated the involvement of Th17 in the mouse model, and found that IL-23, IL-17, and IL-23 mRNAs were upregulated in the psoriatic lesions, strongly suggesting that Th17 was involved in the development of psoriasis, which recapitulated the human psoriatic lesions Recent reports demonstrated that Stat3 activation was induced by IL-22, suggesting that Stat3 could he an ideal therapeutic target for psoriasis. Therefore, we conducted the experiment using a newly-found Stat3 inhibitor, STA21 in our experimental setting. We found that STA21 inhibited the proliferation of human squamous cell lines through down regulation of expression of target genes of Stat3, cyclinD1 and c-myc. Also, STA21 inhibited phosphorylation of Stat3 in these cells. Finally, we elucidated the anti-psoriatic effect of STA21 by showing that its topical treatment ameliorated the development of psoriatic lesions in the mice. These findings provided encouraging evidence that inhibition of Stat3 signaling leads to amelioration of psoriasis, and would be applied for future clinical use. Autoimmune arthritis developed in the kock-in mice with mutated IL-6 receptor gp130 (gp103F759), through which Stat3 signal was predominated GEM, 196, 979, 2002). Topical TPA, treatment of them resulted in the development of psoriatic lesions as found in K5.Stat3C mice, and most interestingly, they developed arthritis toe vicinity of the skin lesions. This finding suggested that Stat3 activation in the psoriatic skin lesions affected the local inflammation of the underlying joints that recapitulated the condition of psoriatic arthritis.