Prof. Hua-Wen Fu
Institute of Molecular and Cellular Biology & Department of Life ScienceNational Tsing Hua University, Hsinchu, Taiwan
Speech Title: Helicobacter pylori neutrophil-activating protein: From a virulence factor to a potential therapeutic target
Abstract: Helicobacter pylori (H. pylori) is a major cause of gastritis and peptic ulcer. Helicobacter pylori neutrophil-activating protein (HP-NAP), a virulence factor of H. pylori, acts as a pathogenic factor by activating a wide range of human leukocytes to induce gastric inflammation caused by H. pylori infection. HP-NAP was initially identified for its ability to stimulate neutrophils to produce reactive oxygen species (ROS). This ROS production is mediated by a pertussis toxin (PTX)-sensitive G protein-coupled receptor (GPCR). In contrast, HP-NAP-induced cytokine secretion by monocytes is mediated by Toll-like receptor 2 (TLR2), a pattern recognition receptor. Recently, we reported that HP-NAP directly interacts with TLR2. In human neutrophils, TLR2 is involved in HP-NAP-induced secretion of interleukin-8 (IL-8) but not HP-NAP-induced ROS production. Interestingly, PTX-sensitive G proteins also contribute to the HP-NAP-induced secretion of IL-8 by neutrophils. In human mast cell line-1 (HMC-1) cells, HP-NAP induces the secretion of histamine and interleukin-6 (IL-6). This secretion depends on PTX-sensitive heterotrimeric G protein-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38-MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt. HP-NAP-induced ROS production and IL-8 secretion by neutrophils and HP-NAP-induced secretion of histamine and IL-6 by mast cells may play critical roles in initiating and modulating gastric inflammatory responses during H. pylori infection. Targeting the receptors involved in HP-NAP signaling offers a potential therapeutic strategy for treating H. pylori-induced gastric inflammation, while directly targeting HP-NAP may provide a straightforward and more effective approach. We have identified a commercial antibody that detects recombinant HP-NAP in addition to its original target protein. This antibody inhibits HP-NAP-induced ROS production and IL-8 secretion by human neutrophils. It also suppresses H. pylori-induced ROS and IL-8 production by human neutrophils, suggesting that blocking HP-NAP activity could help attenuate gastric mucosal inflammation triggered by H. pylori. Taken together, HP-NAP represents a promising therapeutic target for drug development aimed at controlling H. pylori-associated gastric inflammation.