Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 288, Issue 2, Pages C450-C457Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00319.2004
Keywords
superoxide anion; phosphoinositide 3-kinase; Toll-like receptor 4; inflammation
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Primary cultures of guinea pig gastric mucosal cells express NADPH oxidase 1 (Nox1), a homolog of gp91(phox), and produce superoxide anion (O-2(-)) at a rate of similar to 100 nmol . mg protein(-1) . h(-1) in response to Helicobacter pylori (H. pylori) lipopolysaccharide (LPS) from virulent type I strains. The upregulated O-2(-) production also enhances H. pylori LPS-stimulated tumor necrosis factor-alpha or cyclooxygenase-2 mRNA expression, which suggests a potential role for Nox1 in the pathogenesis of H. pylori-associated diseases. The H. pylori LPS-stimulated O-2(-) production in cultured gastric mucosal cells was inhibited by actinomycin D as well as cycloheximide, suggesting that the induction is regulated at the transcriptional level. The LPS treatment not only increased the Nox1 mRNA to a greater extent but also induced expression of the message-encoding, Nox-organizing protein 1 (NOXO1), a novel p47(phox) homolog required for Nox1 activity. In addition, H. pylori LPS activated Rac1; i.e., it converted Rac1 to the GTP-bound state. A phosphoinositide 3-kinase inhibitor, LY-294002, blocked H. pylori LPS-induced Rac1 activation and O-2(-) generation without interfering with the expression of Nox1 and NOXO1 mRNA. O-2(-) production inhibited by LY-294002 was completely restored by transfection of an adenoviral vector encoding a constitutively active Rac1 but not an inactive Rac1 or a constitutively active Cdc42. These findings indicate that Rac1 plays a crucial role in Nox1 activation. Thus the H. pylori LPS-stimulated O-2(-) production in gastric mucosal cells appears to require two distinct events: 1) transcriptional upregulation of Nox1 and NOXO1 and 2) activation of Rac1.
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