Helicobacter pylori-induced IL-33 modulates mast cell responses, benefits bacterial growth, and contributes to gastritis

Abstract

Interleukin (IL)-induced inflammatory responses are critical for the pathogenesis of Helicobacter pylori (H. pylori)-induced gastritis. IL-33 represents a recently discovered proinflammatory cytokine involved in inflammatory diseases, but its relevance to H. pylori-induced gastritis is unknown. Here, we found that gastric IL-33 mRNA and protein expression were elevated in gastric mucosa of both patients and mice infected with H. pylori, which is positively correlated with bacterial load and the degree of gastritis. IL-33 production was promoted via extracellular regulated protein kinases (ERK) signaling pathway activation by gastric epithelial cells in a cagA-dependent manner during H. pylori infection, and resulted in increased inflammation and bacteria burden within the gastric mucosa. Gastric epithelial cell-derived IL-33 promoted TNF-α production from mast cells in vitro, and IL-33 increased TNF-α production in vivo. Increased TNF-α inhibited gastric epithelial cell proliferation, conducing to the progress of H. pylori-associated gastritis and bacteria colonization. This study defined a patent regulatory networks involving H. pylori, gastric epithelial cell, IL-33, mast cell, and TNF-α, which jointly play a pathological effect within the gastric circumstances. It may be a valuable strategy to restrain this IL-33-dependent pathway in the treatment of H. pylori-associated gastritis.

Helicobacter pylori Induces IL-33 Production and Recruits ST-2 to Lipid Rafts to Exacerbate Inflammation

“…Although IL-33 plays a pivotal role in H. pylori infection in mast cells and gastric epithelial cells [10,11], the involvement of membrane rafts in H. pylori -induced IL-33/ST-2 signaling and its effect on inflammation had not been investigated before this study. To the best of our knowledge, this study demonstrates for the first time that sufficient cholesterol level is essential for H. pylori -mediated activation of IL-33/ST-2-induced inflammation.…”

“…Furthermore, NOD1 signaling was implicated in IL-33 production by H. pylori -infected gastric epithelial cells [10]. Moreover, IL-33 also induced TNF-α production by mast cells, which facilitated H. pylori colonization and worsened gastritis [11]. Together, these indicate that IL-33 can intrinsically manipulate the immune system in response to H. pylori infection.…”

IL33 and Mast Cells—The Key Regulators of Immune Responses in Gastrointestinal Cancers?

“…Chronic inflammation or infection often precedes neoplastic transformation. Accordingly, IL33 expression is elevated in colonic epithelial cells and myofibroblasts of ulcerative colitis patients (83,84) and in the chronically inflamed stomachs of patients infected with H. pylori or during bouts of acute gastritis (85,86). Meanwhile, increased MC numbers are readily detected in patients with ulcerative colitis, gastritis and various other inflammatory disorders of the GI tract [reviewed in (87)] and have been attributed a disease-promoting role (88).…”

Arrestin domain containing 3 promotes Helicobacter pylori–associated gastritis by regulating protease-activated receptor 1

“…pylori –associated gastritis remain unclear. The interaction between bacteria and gastric epithelial cells (GECs) might be a key determinant, implied especially by the critical roles of the bacterial virulence factor cytotoxin associated gene A ( cagA ) protein ( 3 , 4 ).…”