Helicobacter felis-induced gastritis was suppressed in mice overexpressing thioredoxin-1

Abstract

Thioredoxin-1 (TRX-1) is a redox-active protein involved in scavenging reactive oxygen species and regulating redox-sensitive transcription factors. TRX-1 is induced in various inflammatory conditions and shows cytoprotective action. We investigated the roles of TRX-1 in the host defense mechanism against Helicobacter felis (H. felis) infection. Transgenic (TG) mice overexpressing human TRX-1 and wild-type (WT) mice were orally inoculated with H. felis. After 2 months, histology, oxidative damage, and gene expression of several cytokines, including macrophage inflammatory protein-2 (MIP-2), a murine equivalent to interleukin (IL)-8, in the gastric mucosa were investigated. Furthermore, the effects of TRX-1 on oxidative stress and neutrophil migration were studied both in vivo and in vitro. The gastric mucosa was thickened in H. felis-infected WT mice, but not in infected TRX-1-TG mice. Histologically, all H. felis-infected WT mice developed moderate-to-severe gastritis, whereas the development of gastritis was significantly suppressed in infected TRX-1-TG mice. Oxidative damage markers, 8-hydroxy-2 0 -deoxyguanosine and malondialdehyde, increased in the stomach of infected WT mice, but not TRX-1-TG mice. Upregulation of IL-1b and tumor necrosis factor-a gene expression in H. felisinfected TRX-1-TG mice was significantly lower than in WT mice. However, upregulation of MIP-2 and IL-7 was not different between the two groups. TRX-1 suppressed oxidative cytotoxicity and DNA damage, and inhibited neutrophil migration both in vivo and in vitro. The present study suggests that overexpression of TRX-1 suppresses H. felis-induced gastritis by inhibiting chemotaxis of neutrophils and reducing oxidative stress.

Conditional Deletion of IκB-Kinase-β Accelerates Helicobacter-Dependent Gastric Apoptosis, Proliferation, and Preneoplasia

“…Thus, the loss of Ikkβ resulted in increased oxidative stress, DNA damage and cellular necrosis. Oxidative stress induced by ROS has an important role in the formation of gastric injury by Helicobacter infection 32. 18 months post H. felis infection, the gastric mucosa of Ikkβ Δstom mice also exhibited a higher number of anti-8-OHdG-positive cells than Ikkβ F/F mice (Figure 6 B ), suggesting that loss of Ikkβ is likely associated with the ROS accumulation and subsequent DNA damage in this model.…”

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

“…Nevertheless, it is noteworthy that administration of TRX during allergen-challenging phase, but not allergen-sensitization phase, suppressed airway inflammation, indicating that TRX could suppress Th2-driven inflammation irrespectively of initial development of Th2 immunity [23]. When all of the data are considered together, there are a number of studies that demonstrated a protective role for endogenous and/or exogenous TRX in different models of inflammatory diseases including autoimmune myocarditis [34], diabetes [18,35], gastritis [36], colitis [32] as well as asthma [23,37]. Thus, it seems unlikely that the sole function of TRX to negatively regulate inflammatory reactions is mediated through the modulation of Th1/Th2 immunity.…”

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

“…TRX-1 shows cytoprotective action in various inflammatory conditions. For example, TRX-1 reduces DNA damage and neutrophil aggregation in the Helicobacter felis-infected stomach, suggesting a protective role in murine gastritis (144).…”