Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p-STAT3 in Helicobacter pylori-associated gastritis

FASEB J. 2020 Jan;34(1):1169-1181. doi: 10.1096/fj.201900464RR. Epub 2019 Nov 29.

Abstract

BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pylori-infected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4+ T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.

Keywords: Helicobacter pylori; cagA; BHLHE40; CXCL12; p‐STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • CD4-Positive T-Lymphocytes / cytology
  • Cell Nucleus / metabolism
  • Chemokine CXCL12 / metabolism*
  • Epithelial Cells / metabolism*
  • Female
  • Gastric Mucosa / metabolism
  • Gastric Mucosa / microbiology
  • Gastritis / metabolism
  • Gastritis / microbiology*
  • Gene Expression Regulation
  • Helicobacter Infections / metabolism*
  • Helicobacter pylori
  • Homeodomain Proteins / metabolism*
  • Humans
  • Inflammation
  • Mice
  • Mice, Inbred C57BL
  • STAT3 Transcription Factor / metabolism*
  • Stomach / microbiology
  • Up-Regulation

Substances

  • BHLHE40 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlhe40 protein, mouse
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Homeodomain Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse