Renin Promotes STAT4 Phosphorylation to Induce IL-17 Production in Keratinocytes of Oral Lichen Planus

Xuejun Ge; Hanting Xie; Tivoli Nguyen; Bin Zhao; Jing Xu; Jie Du

doi:10.1016/j.isci.2020.100983

Renin Promotes STAT4 Phosphorylation to Induce IL-17 Production in Keratinocytes of Oral Lichen Planus

iScience. 2020 Apr 24;23(4):100983. doi: 10.1016/j.isci.2020.100983. Epub 2020 Mar 13.

Authors

Xuejun Ge¹, Hanting Xie², Tivoli Nguyen³, Bin Zhao⁴, Jing Xu², Jie Du⁵

Affiliations

¹ Department of Endodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China.
² Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, China.
³ Division of Biological Sciences, Department of Medicine, The University of Chicago, Chicago, IL, USA.
⁴ Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, NO. 56 Xinjian South Road, Taiyuan, Shanxi 030001, China; Department of Prosthodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China; Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan, Shanxi, China.
⁵ Department of Oral Medicine, Shanxi Medical University School and Hospital of Stomatology, NO. 56 Xinjian South Road, Taiyuan, Shanxi 030001, China; Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan, Shanxi, China. Electronic address: dj1243@hotmail.com.

Abstract

Interleukin-17 (IL-17) is highly expressed in the epithelial layer of oral lichen planus (OLP), but the underlying mechanism for IL-17 overexpression remains unknown. Here, we identify renin that is induced by NF-κB pathway contributes to the increase of IL-17 in human oral keratinocytes (HOKs). We describe that the release of cellular renin leads to the phosphorylation of Janus kinase 2 (JAK2) protein. The phosphorylated JAK2 recruits and activates the signal transducer and activator of transcription 4 (STAT4) by phosphorylating STAT4's tyrosine residue 693 (Tyr693). The now-activated STAT4 translocates into nucleus and binds to the promoter region of IL-17 gene in HOKs. Genetic interference of renin restores IL-17 levels in OLP cell models. Collectively, our results reveal that renin upregulates IL-17 expression by enhancing STAT4 phosphorylation. This discovery unveils an underpinning by which IL-17 is increased in oral keratinocytes and provides potential targeted therapies for OLP patients.

Keywords: Immunology; Molecular Biology; Oral Medicine.