Heme oxygenase-1 is a critical regulator of nitric oxide production in enterohemorrhagic Escherichia coli-infected human enterocytes.
Enterohemorrhagic Escherichia coli (EHEC) are the causative agent of hemolytic-uremic syndrome. In the first stage of the infection, EHEC interact with human enterocytes to modulate the innate immune response. Inducible NO synthase (iNOS)-derived NO is a critical mediator of the inflammatory response of the infected intestinal mucosa. We therefore aimed to analyze the role of EHEC on iNOS induction in human epithelial cell lines. In this regard, we show that EHEC down-regulate IFN-gamma-induced iNOS mRNA expression and NO production in Hct-8, Caco-2, and T84 cells. This inhibitory effect occurs through the decrease of STAT-1 activation. In parallel, we demonstrate that EHEC stimulate the rapid inducible expression of the gene hmox-1 that encodes for the enzyme heme oxygenase-1 (HO-1). Knock-down of hmox-1 gene expression by small interfering RNA or the blockade of HO-1 activity by zinc protoporphyrin IX abrogated the EHEC-dependent inhibition of STAT-1 activation and iNOS mRNA expression in activated human enterocytes. These results highlight a new strategy elaborated by EHEC to control the host innate immune response.
Vareille
Marjolaine
M
Institut National de la Recherche Agronomique, Unité de Microbiologie UR454, Saint-Genès-Champanelle, France.
Rannou
François
F
Thélier
Natacha
N
Glasser
Anne-Lise
AL
de Sablet
Thibaut
T
Martin
Christine
C
Gobert
Alain P
AP
D045744:Cell Line, Tumor; D020895:Enterocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D054324:Enterohemorrhagic Escherichia coli / Q000472:pathogenicity* / Q000502:physiology; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism
D011524:Protoporphyrins; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C017803:zinc protoporphyrin; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1