The TNF-Alpha Inducing Protein is Associated With Gastric Inflammation and Hyperplasia in a Murine Model of Helicobacter pylori Infection

Abstract

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the human stomach leading to the development of chronic gastritis, peptic ulcers and gastric adenocarcinoma. A combination of host, environment and bacterial virulence factors contribute to disease development. The H. pylori TNFα inducing protein (Tipɑ) is a virulence factor shown to induce multiple pro-inflammatory cytokines in addition to TNFα in vitro. The goal of the present study was to elucidate the role of Tipα in promoting inflammation in vivo and to identify the molecular pathways associated with Tipα associated virulence. Mice were infected with wild-type Sydney strain (SS1) or a tipα mutant (Δtipα) for 1 month and 4 months. We also completed a second 4 months infection including a 1:1 SS1 to Δtipα co-infected group in addition to SS1 and Δtipα infected groups. The expression of TNFα, and KC were significantly higher in the SS1 infected group compared to both uninfected control (naïve) and Δtipα groups. Mice infected with Tipα expressing SS1 induced more severe histological gastritis and developed hyperplasia compared to Δtipα infected mice. Microarray analysis of gastric epithelial cells co-cultured with recombinant Tipα (rTipα) demonstrates up-regulation of the NFκB pathway. This data suggest Tipα plays an important role in H. pylori induced inflammation.

Unraveling the crystal structure of the HpaA adhesin: insights into cell adhesion function and epitope localization of a Helicobacter pylori vaccine candidate

“…Our data establishe that HpaA stimulation results in a 1.3-fold increase in TNF-α cytokine induction in AGS cells and a 2.8-fold increase in macrophage cells. Significantly, this response closely mirrors the positive control reaction triggered by the TNF-α inducing protein, Tipα, a bacterial effector utilized by H. pylori to sustain chronic inflammation in gastric tissues ( 39 ). Furthermore, we detect additional IL8 responses in macrophages upon HpaA stimulation, demonstrating once again comparable response to the Tipα effector.…”

Pharmacological and molecular analysis of the effects of Huangqi Jianzhong decoction on proliferation and apoptosis in GES-1 cells infected with H. pylori

“…HQJZD may inhibit H. pylori activity by regulating lipids and atherosclerotic pathways. Both TNF-α and NF-κB play key roles in inflammation and cancer development, and the H. pylori -specific virulence factor, Tip-α, is a TNF-α-inducing protein that participates in TNF-α and NF-κB pathways as an oncogenic factor mediating inflammation and immune responses, and has an important part in triggering chronic gastritis, hyperplasia, and gastric cancer ( Morningstar-Wright et al, 2022 ).…”

In Peripheral Blood Mononuclear Cells Helicobacter pylori Induces the Secretion of Soluble and Exosomal Cytokines Related to Carcinogenesis

“…In human macrophages, the hypothetical protein 1173 (HP1173) from H. pylori strain 26695 stimulates the MAPK signaling pathways, leading to the activation of NF-κB and activator protein-1 (AP-1), and thus to the secretion of TNF-α, chemokine C-X-C motif chemokine ligand 8 (CXCL8) and IL-1β [ 35 ]. In a murine model, it was found that the TNF-α-inducing protein (Tip α) of H. pylori activates the NF-κB signaling pathway, and contributes to the pro-inflammatory response, gastritis development, hyperplasia, and gastric cancer [ 36 ]. Moreover, H. pylori CagA reduces the secretion of IL-12p40, and increases the expression of IL-10, which shows pro- and anti-inflammatory effects, promoted by this oncoprotein [ 37 ].…”