Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation.
Helicobacter pylori infection of the stomach elicits a vigorous but ineffective host immune and inflammatory response, resulting in persistence of the bacterium for the life of the host. We have reported that in macrophages, H. pylori up-regulates inducible NO synthase (iNOS) and antimicrobial NO production, but in parallel there is induction of arginase II, generating ornithine, and of ornithine decarboxylase (ODC), generating polyamines. Spermine, in particular, has been shown to restrain immune response in activated macrophages by inhibiting proinflammatory gene expression. We hypothesized that spermine could prevent the antimicrobial effects of NO by inhibiting iNOS in macrophages activated by H. pylori. Spermine did not affect the up-regulation of iNOS mRNA levels but in a concentration-dependent manner significantly attenuated iNOS protein levels and NO production. Reduction in iNOS protein was due to inhibition of iNOS translation and not due to iNOS degradation. ODC knockdown with small interfering (si) RNA resulted in increased H. pylori-stimulated iNOS protein expression and NO production without altering iNOS mRNA levels. When macrophages were cocultured with H. pylori, killing of bacteria was enhanced by transfection of ODC siRNA and prevented by addition of spermine. These results identify a mechanism of immune dysregulation induced by H. pylori in which stimulated spermine synthesis by the arginase-ODC pathway inhibits iNOS translation and NO production, leading to persistence of the bacterium and risk for peptic ulcer disease and gastric cancer.
Bussière
Françoise I
FI
Department of Medicine, Division of Gastroenterology, and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, USA.
Chaturvedi
Rupesh
R
Cheng
Yulan
Y
Gobert
Alain P
AP
Asim
Mohammad
M
Blumberg
Darren R
DR
Xu
Hangxiu
H
Kim
Preston Y
PY
Hacker
Amy
A
Casero
Robert A
RA
Wilson
Keith T
KT
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D016480:Helicobacter pylori / Q000276:immunology* / Q000378:metabolism; D007107:Immune System / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D013096:Spermine / Q000378:metabolism / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000382:microbiology; D014162:Transfection; D015854:Up-Regulation
D034741:RNA, Small Interfering; D013096:Spermine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse