Conditional Deletion of IkappaB-Kinase-beta Accelerates Helicobacter-Dependent Gastric Apoptosis, Proliferation, and Preneoplasia

Abstract

Background & Aims:

The nuclear factor κB (NF-κB)/IκB-kinase-β (IKKβ) pathway has been shown to represent a key link between inflammation and cancer, inducing pro-inflammatory cytokines in myeloid cells and anti-apoptotic pathways in epithelial cells. However, the role of NF-κB pathway in gastric carcinogenesis and injury has not been well-defined. We derived mice with a conditional knockout of IKKβ in gastric epithelial cells (GECs) and myeloid cells, and examined responses to ionizing radiation (IR) and Helicobacter felis infection. Methods:

IkkβΔstom mice were generated by crossing Foxa3-Cre mice to IkkβF/F mice. Cellular stress was induced with IR and H felis in IkkβΔstom, IkkβF/F, and cis-NF-κB–enhanced green fluorescent protein (GFP) reporter mice. Gastric histopathology, apoptosis, proliferation, necrosis, reactive oxygen species, and expression of cytokines, chemokines, and anti-apoptotic genes were assessed. The role of myeloid IKKβ in these models was studied by crosses with LysM-Cre mice. Results:

NF-κB activity was upregulated in myeloid cells with acute H felis infection, but in GECs by IR or long-term H felis infection during progression to dysplasia. Deletion of IKKβ in GECs led to increased apoptosis, reactive oxygen species, and cellular necrosis, and resulted in up-regulation of interleukin-1α and down-regulation of anti-apoptotic genes. Loss of IKKβ in GECs resulted in worse inflammation and more rapid progression to gastric preneoplasia, while loss of IKKβ in myeloid cells inhibited development of gastric atrophy. Conclusions:

The loss of IKKβ/NF-κB signaling in GECs results in increased apoptosis and necrosis in response to cellular stress, and accelerated development of dysplasia by Helicobacter infection.