Differential roles of ASK1 and TAK1 in Helicobacter pylori-induced cellular responses

Infect Immun. 2013 Dec;81(12):4551-60. doi: 10.1128/IAI.00914-13. Epub 2013 Sep 30.


The mitogen-activated protein kinase (MAPK) signaling pathway regulates various cellular functions, including those induced by Helicobacter pylori. TAK1 is an upstream MAPK kinase kinase (MAP3K) required for H. pylori-induced MAPK and NF-κB activation, but it remains unclear whether other MAP3Ks are involved in H. pylori-induced cellular responses. In this study, we focused on the MAP3K ASK1, which plays a critical role in gastric tumorigenesis. In gastric epithelial cells, H. pylori activates ASK1 in a reactive oxygen species (ROS)- and cag pathogenicity island-dependent manner, and ASK1 regulates sustained JNK activation and apoptosis induced by H. pylori. In contrast, TAK1 regulates H. pylori-mediated early JNK activation and cytokine production. We also found reciprocal regulation between ASK1 and TAK1 in H. pylori-related responses, whereby inhibition of TAK1 or downstream p38 MAPK activates ASK1 through ROS production, and ASK1 suppresses TAK1 and downstream NF-κB activation. We identified ROS/ASK1/JNK as a new signaling pathway induced by H. pylori, which regulates apoptotic cell death. The balance of ASK1-induced apoptosis and TAK1-induced antiapoptotic or inflammatory responses may determine the fate of epithelial cells infected with H. pylori and thus be involved in the pathogenesis of gastritis and gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology
  • Carcinogenesis
  • Cell Line
  • Enzyme Activation
  • Epithelial Cells / metabolism
  • Gastric Mucosa / metabolism
  • Helicobacter Infections / immunology
  • Helicobacter Infections / metabolism*
  • Helicobacter pylori / immunology
  • Helicobacter pylori / metabolism*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • MAP Kinase Kinase Kinases / metabolism*
  • MAP Kinase Signaling System / immunology*
  • NF-kappa B / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Stomach Neoplasms / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • NF-kappa B
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • MAP3K5 protein, human