The PDIA3-STAT3 protein complex regulates IBS formation and development via CTSS/MHC-II pathway-mediated intestinal inflammation
Chunyan Weng,
Jingli Xu,
Xiao Ying,
Shaopeng Sun,
Yue Hu,
Xi Wang,
Chenghai He,
Bin Lu,
Meng Li
Affiliations
Chunyan Weng
Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
Jingli Xu
Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
Xiao Ying
Department of Gastroenterology, The First People's Hospital of Yongkang, Jinhua 321300, Zhejiang Province, China
Shaopeng Sun
Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
Yue Hu
Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China
Xi Wang
Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China; Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou, 310006, China
Chenghai He
Department of Internal Medicine, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou, Zhejiang Province, China
Bin Lu
Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China; Corresponding author.
Meng Li
Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310000, Zhejiang Province, China; Corresponding author.
Irritable bowel syndrome (IBS) is a persistent functional gastrointestinal disorder characterised by abdominal pain and altered patterns of defecation. This study aims to clarify an increase in the expression and interaction of protein disulfide-isomerase A3 (PDIA3) and Signal Transducer and Activator of Transcription 3 (STAT3) within the membrane of dendritic cells (DCs) from individuals with IBS. Mechanistically, the heightened interaction between PDIA3 and STAT3 at the DC membrane results in reduced translocation of phosphorylated STAT3 (p-STAT3) into the nucleus. The reduction of p-STAT3 to nuclear transport subsequently increased the levels of cathepsin S (CTSS) and major histocompatibility complex class II (MHC-II). Consequently, activated DCs promote CD4+ T cell proliferation and cytokine secretion, including interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-9 (IL-9), and tumour necrosis factor-alpha (TNF-α), thereby contributing to the development of IBS. Importantly, the downregulation of PDIA3 and the administration of punicalagin (Pun), a crucial active compound found in pomegranate peel, alleviate IBS symptoms in rats, such as increased visceral hypersensitivity and abnormal stool characteristics. Collectively, these findings highlight the involvement of the PDIA3-STAT3 protein complex in IBS, providing a novel perspective on the modulation of immune and inflammatory responses. Additionally, this research advances our understanding of the role and mechanisms of PDIA3 inhibitors, presenting new therapeutic possibilities for managing IBS.
