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The proinflammatory cytokines IL‐1β and TNF‐α modulate corneal epithelial wound healing through p16 Ink4a suppressing STAT3 activity
Author(s) -
Wang Xiaolei,
Zhang Songmei,
Dong Muchen,
Li Yunqiu,
Zhou Qingjun,
Yang Lingling
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29823
Subject(s) - proinflammatory cytokine , corneal epithelium , stat3 , wound healing , tumor necrosis factor alpha , stat protein , cancer research , cytokine , epithelium , medicine , immunology , inflammation , signal transduction , biology , microbiology and biotechnology , pathology
The proinflammatory cytokines interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α) are involved in the corneal inflammatory response and wound healing following corneal injuries. However, the mechanism by which proinflammatory cytokines modulate corneal epithelial wound healing remains unclear. In this study, we found that IL‐1β or TNF‐α was transiently elevated during corneal epithelial wound healing in mice. After corneal epithelial debridement, persistent treatment with IL‐1β or TNF‐α restrained the level of phosphorylated signal transducer and activator of transcription 3 (p‐STAT3) and boosted the level of cell cycle inhibitor p16 Ink4a , resulting in impaired corneal epithelial repair. When p16 Ink4a was deleted, the p‐STAT3 level in corneal epithelium was enhanced and corneal epithelial wound healing was clearly accelerated. In diabetic mice, IL‐1β, TNF‐α, and p16 Ink4a appeared a sustained and strong expression in the corneal epithelium, and p16 Ink4a knockdown partially reverted the defective diabetic corneal epithelial repair. Furthermore, immunoprecipitation proved that p16 Ink4a interacted with p‐STAT3 and thus possibly suppressed the STAT3 activity. Our findings revealed a novel mechanism that the proinflammatory cytokines modulate corneal epithelial wound healing via the p16 Ink4a ‐STAT3 signaling.