PLK1‐activating IFI16–STING–TBK1 pathway induces apoptosis of intestinal epithelial cells in patients with intestinal Behçet's syndrome

• Published in: The FEBS journal 2024-08, Vol.291 (15), p.3432-3453
• Main Authors: Bao, Hua‐fang, She, Chun‐hui, Hou, Cheng‐cheng, Ji, Da‐nian, Hu, Dan, Zou, Jun, Shen, Yan, Jian, Lei‐lei, Cai, Jian‐fei, Ye, Jing‐fen, Luo, Dan, Ma, Hai‐fen, Guan, Jian‐long
• Format: Article
• Language: English
• Subjects: agonists; Apoptosis; Behcet's syndrome; Behçet's syndrome; Caspase-3; Cell culture; coculture; cytokines; Epithelial cells; Epithelium; Gene sequencing; humans; IFI16; Immunology; Inflammation; Interferon; interferons; Intestine; intestines; Kinases; Leukocytes (mononuclear); Monoclonal antibodies; necrosis; neoplasms; Pathogenesis; Peripheral blood mononuclear cells; PLK1; Polo-like kinase 1; protein content; Proteins; quantitative polymerase chain reaction; RNA; secretion; Stimulators; STING; Therapeutic targets; therapeutics; Tumor necrosis factor; Tumor necrosis factor-TNF; Vein & artery diseases
• ISSN: 1742-464X; 1742-4658; 1742-4658
• DOI: 10.1111/febs.17147

Inflammatory signals from immunological cells may cause damage to intestinal epithelial cells (IECs), resulting in intestinal inflammation and tissue impairment. Interferon‐γ‐inducible protein 16 (IFI16) was reported to be involved in the pathogenesis of Behçet's syndrome (BS). This study aimed to investigate how inflammatory cytokines released by immunological cells and IFI16 participate in the pathogenesis of intestinal BS. RNA sequencing and real‐time quantitative PCR (qPCR) showed that the positive regulation of tumor necrosis factor‐α (TNF‐α) production in peripheral blood mononuclear cells (PBMCs) of intestinal BS patients may be related to the upregulation of polo like kinase 1 (PLK1) in PBMCs (P = 0.012). The plasma TNF‐α protein level in intestinal BS was significantly higher than in healthy controls (HCs; P = 0.009). PBMCs of intestinal BS patients and HCs were co‐cultured with human normal IECs (NCM460) to explore the interaction between immunological cells and IECs. Using IFI16 knockdown, PBMC‐NCM460 co‐culture, TNF‐α neutralizing monoclonal antibody (mAb), stimulator of interferon genes (STING) agonist 2′3′‐cGAMP, and the PLK1 inhibitor SBE 13 HCL, we found that PLK1 promotes the secretion of TNF‐α from PBMCs of intestinal BS patients, which causes overexpression of IFI16 and induces apoptosis of IECs via the STING–TBK1 pathway. The expressions of IFI16, TNF‐α, cleaved caspase 3, phosphorylated STING (pSTING) and phosphorylated tank binding kinase 1 (pTBK1) in the intestinal ulcer tissue of BS patients were significantly higher than that of HCs (all P