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GROWTH, DIFFERENTIATION, AND APOPTOSIS

Helicobacter pylori lipopolysaccharide activates Rac1 and transcription of NADPH oxidase Nox1 and its organizer NOXO1 in guinea pig gastric mucosal cells

Departments of ¹Nutritional Physiology and ³Stress Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima; ²Medical Institute of Bioregulation, Kyushu University, Fukuoka; ⁴Department of Infectious Diseases, National Research Institute for Child Health and Development, Tokyo; and ⁵Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan

Submitted 6 July 2004 ; accepted in final form 30 September 2004

Primary cultures of guinea pig gastric mucosal cells express NADPH oxidase 1 (Nox1), a homolog of gp91^phox, and produce superoxide anion (O₂^–) at a rate of 100 nmol·mg protein^–1·h^–1 in response to Helicobacter pylori (H. pylori) lipopolysaccharide (LPS) from virulent type I strains. The upregulated O₂^– production also enhances H. pylori LPS-stimulated tumor necrosis factor- 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 O₂^– 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 O₂^– generation without interfering with the expression of Nox1 and NOXO1 mRNA. O₂^– 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 O₂^– production in gastric mucosal cells appears to require two distinct events: 1) transcriptional upregulation of Nox1 and NOXO1 and 2) activation of Rac1.

superoxide anion; phosphoinositide 3-kinase; Toll-like receptor 4; inflammation

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