Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3‐Ser727 phosphorylation as a modulator of transcriptional activity

Abstract

Jak/Tyk proteins have recently aroused as possible therapeutic targets for the treatment of psoriasis. In psoriasis, these proteins signal through STAT molecules including STAT3, and STAT3 expression and activation has been shown augmented in psoriatic lesions. Here, we characterized the expression of Jak/Tyk proteins in lesional compared with non-lesional psoriatic skin. Jak1, Jak2 mRNA and protein and Tyk2 mRNA appeared to be downregulated, whereas Jak3 mRNA expression was increased. Moreover, STAT3 expression and activation was examined in psoriasis. STAT3 is activated at two phosphorylation sites: Tyr705 and Ser727. Both phosphorylation sites were phosphorylated in lesional psoriatic skin. The activation of STAT3 by Jak/Tyk proteins was studied in cultured normal human keratinocytes. Tyr705 phosphorylation was induced by IL-6 and IL-20 in a Jak2-dependent manner, and moreover, phosphorylation of Tyr705 produced a strong increase in STAT3 transcriptional activity. TNFα, 12-O-Tetradecanoylphorbol 13-acetate (TPA) and UVB irradiation induced Ser727 phosphorylation of STAT3 in an ERK1/2- and p38 MAPK-dependent manner, which resulted in a modulatory effect on STAT3 transcriptional activity. Our results demonstrate how different signalling pathways can integrate and lead to regulation of STAT3 transcriptional activity.

IκBζ is a key driver in the development of psoriasis

“…Intracellular signaling pathways and their role in psoriasis have recently attracted much interest, and signaling pathways such as the NF-κB, JAK/STAT, and p38 MAPK pathway have been demonstrated to be altered in psoriatic skin (11,(28)(29)(30). Here, we identify for the first time to our knowledge IκBζ as a key regulator in the development of psoriasis and as an important transcriptional coactivator mediating downstream effects of IL-17A.…”

The Role of p38 MAPK in Rheumatic Diseases

“…These cytokines are also under direct regulation of the p38 pathway as well [83,84]. p38 MAPK-induced phosphorylation of STAT-3 and of STAT-1 at serine 727 has also been demonstrated in lesional psoriatic skin [85,86]. STAT-3, in particular, has been described as the crucial link between activated keratinocytes and immunocytes required for the development of psoriasis in a novel transgenic mouse model [87].…”

Emerging treatment options for psoriasis

“…[20][21][22][23][24][25] Tofacitinib is an inhibitor of the JAK1 and JAK3 signaling pathway. Inhibition of JAK3 blocks signal transduction of a number of cytokines (IL-2, 4, 7, 9, 15, and 21), resulting in modulation of lymphocyte function and survival.…”