Quantitative Proteomics of Keratinocytes Reveals IL-6 Promotes Psoriasis through the JAK/PI3K/AKT Pathway

Abstract

Background: Psoriasis is a common and recurrent chronic inflammatory skin disease, which is characterized by high expression of Keratin 17 (K17) of keratinocytes and is considered a Th cell-mediated immune disease. As a major effector of Th cells, interleukin 6 (IL-6) has been found to play a significant role in developing psoriasis by promoting inflammation and keratinocyte proliferation. However, the mechanism has not been fully understood. Methods: In this study, we investigated the correlation between IL-6 and K17 expression in GEO datasets, psoriasis mouse model, and human keratinocytes, respectively. Using a label-free quantitative proteomic approach, we determined the effect of IL-6 stimulation on the proteomics profile of keratinocytes and identified the potential underlying signaling pathways. Further experimental validation was performed using inhibitors. Results: The expression levels of K17 and IL-6 were positively correlated. A total of 2876 proteins were quantified in IL-6-treated human keratinocyte HaCaT, of which 98 were downregulated, while 135 were upregulated. Bioinformatic analysis revealed a significant enrichment of inflammation-related biological functions and the JAK/PI3K pathway. Experimental validation using a specific antagonist of JAK and PI3K demonstrated that keratinocyte proliferation and Keratin 17 induction by IL-6 depended on the JAK/PI3K/AKT pathway. Conclusions: Our study demonstrated that IL-6 promoted psoriasis through the JAK/PI3K/AKT pathway, which might be a potential target for psoriasis.