Helicobacter hepaticus infection induces chronic hepatitis and fibrosis in male BALB/c mice via the activation of NF‐κB, Stat3, and MAPK signaling pathways

Abstract

Background It has been documented that Helicobacter hepaticus (H hepaticus) infection is linked to chronic hepatitis and liver cancer. However, our understanding of the molecular mechanisms underlying progression of the H hepaticus‐induced hepatic inflammation to cellular hepatocarcinoma is still limited. Materials and methods In our study, male BALB/c mice were infected by H hepaticus for 8, 12, 16, 20, and 24 weeks. Histopathology, H hepaticus colonization dynamics, select signaling pathways, and expression of key inflammatory cytokines in the liver were examined. Results We found that H hepaticus was detectible in feces of mice at 7 days postinfection (DPI) by PCR, but it was not detected in the livers by PCR until 8 weeks postinfection (WPI). In addition, abundance of colonic and hepatic H hepaticus was progressively increased over the infection duration. H hepaticus‐induced hepatic inflammation and fibrosis were aggravated over the infection duration, and necrosis or cirrhosis developed in the infected liver at 24 WPI H hepaticus infection increased levels of alanine aminotransferase and aspartate aminotransferase. Moreover, mRNA levels of Il‐6 and Tnf‐α were significantly elevated in the livers of H hepaticus‐infected mice compared to uninfected control from 8 WPI to 24 WPI. Furthermore, Stat3, nuclear factor‐κB (p65), and MAPK (Erk1/2 and p38) were activated by H hepaticus infection. Conclusions These data demonstrated that male BALB/c mice can be used as a new mouse model of H hepaticus‐induced liver diseases and that the H hepaticus‐induced liver injury is triggered by NF‐κB, Jak‐Stat, and MAPK signaling pathways.

Dietary intake of walnut prevented <i>Helicobacter pylori</i>-associated gastric cancer through rejuvenation of chronic atrophic gastritis

“…(29)(30)(31) Among mechanisms in H. pylori-carcinogenesis, including NF-kB based oxidative stress, cytokines mediated mutagenesis, apoptosis induced atrophic changes through loss of parietal cells and some gastric stem cells, and more carcinogenic actions like CagA oncogenic proteins, (32,33) it has been well documented that H. pylori infection causes activation of STAT3 activation, forms a dimer, trans-locates to nucleus, and functions as transcription factor to regulate the target genes implicated in H. pylori-associated inflammation and carcinogenesis subsequent to IL-6. (27,(34)(35)(36) Furthermore, CagA oncogenic cytotoxin from H. pylori led to significant cytokine signaling pathways via MAPK activation and is responsible for gastric inflammation and carcinogenes is including increased cell proliferation, angiogenesis, inflammation, inhibition of immunocytes, and epithelial cell apoptosis. (37) Among these cytokines, IL-6, IL-6R, and gp130 with subsequent JAKs/STAT3 activation are representationally dysregulated pathways in H. pylori infection.…”

Walnut polyphenol extracts inhibit <i>Helicobacter pylori</i>-induced STAT3^Tyr705 phosphorylation through activation of PPAR-γ and SOCS1 induction

“…Walnut extract inhibited H. pylori induced IL 6 and addi tional inflammatory mediators including COX 2, c Myc, TNF α. IL-6 is one of core mediators implicated in inflammatory and carcinogenic process in H. pylori associated gastric carcinogenesis via NF-kB, STAT3, and MAPK signaling pathways. (5) As seen in the Fig. 1A dealing with the changes of IL-6 mRNA along with H. pylori infection in AGS cells, H. pylori infection significantly increased IL-6 mRNA after 12 h and persisted up to 24 h. In this time, 24 h after 50 MOI H. pylori infection, increased IL-6 mRNA was significantly decreased with increasing doses of WPE ( Fig.…”

“…(1) Among mechanisms in H. pylori-carcinogenesis, including NF-kB based oxidative stress, cytokines mediated mutagenesis, apoptosis induced atrophic changes, and more carcinogenic actions, (2,3) it has been well documented as molecular pathomechanism that H. pylori infection causes the activation of signal transducer and activator of transcription 3 (STAT3), STAT3 phosphorylated on Tyr705 residue (p-STAT3 Tyr705 ), forms a dimer, translocates to nucleus, and functions as transcription factor to regulate the target genes implicated in H. pylori-associated inflammation and carcinogenesis subsequent to IL-6 activation. (4)(5)(6)(7) Though STAT3 Ser727 phosphorylation can be pathogenically involved in oxidative stress and malignant transformation relevant to H. pylori infection since STAT3 Ser727 localizes in mitochondria and associates with Ras dependent oncogenic transformation, p-STAT3 Tyr705 had been revealed to be implicated in either Barrett's esophagus and H. pylori-associated oncogenic inflammation. (8,9) CagA cytotoxin from H. pylori led to significant cytokine signaling pathways via MAPK activation and is responsible for gastric inflammation and carcinogenesis including increased cell proliferation, angiogenesis, inflammation, inhibition of immunocytes, and epithelial cell apoptosis.…”

Review: Other Helicobacter species

“…A new mouse model of H. hepaticus ‐induced liver chronic hepatitis and fibrosis was described in male BALB/c mice. In this model, H. hepaticus ‐associated hepatic inflammation and fibrosis worsened over time and these liver injuries were triggered via the activation of NF‐κB, JAK‐STAT, and MAPK signaling pathways 18 . Male BALB/c mice infected with H. hepaticus presented long‐term high IL‐33 mRNA and protein levels.…”