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This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/C450    most recent 00319.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (44) Citing Articles via Google Scholar Google Scholar Articles by Kawahara, T. Articles by Rokutan, K. Search for Related Content PubMed PubMed Citation Articles by Kawahara, T. Articles by Rokutan, K.

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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