Campylobacter jejuni induces colitis through activation of mammalian target of rapamycin signaling.

Publication Type:

Featured

Source:

Gastroenterology, Volume 142, Issue 1, p.86-95.e5 (2012)

Keywords:

Animalsdigestive disease, digestive deseases Campylobacter Infectionsdigestive disease, digestive deseases Campylobacter jejunidigestive disease, digestive deseases CD4-Positive T-Lymphocytesdigestive disease, digestive deseases Cells, Cultureddigestive disease, digestive deseases Chemokine CXCL2digestive disease, digestive deseases Colitisdigestive disease, digestive deseases Colondigestive disease, digestive deseases Disease Models, Animaldigestive disease, digestive deseases Enzyme Activationdigestive disease, digestive deseases Green Fluorescent Proteinsdigestive disease, digestive deseases In Situ Hybridization, Fluorescencedigestive disease, digestive deseases Inflammation Mediatorsdigestive disease, digestive deseases Injections, Intraperitonealdigestive disease, digestive deseases Interleukin-10digestive disease, digestive deseases Interleukin-17digestive disease, digestive deseases Interleukin-1betadigestive disease, digestive deseases Micedigestive disease, digestive deseases Mice, 129 Straindigestive disease, digestive deseases Mice, Inbred C57BLdigestive disease, digestive deseases Mice, Knockoutdigestive disease, digestive deseases Mice, Transgenicdigestive disease, digestive deseases Microscopy, Electron, Transmissiondigestive disease, digestive deseases Neutrophil Infiltrationdigestive disease, digestive deseases Neutrophilsdigestive disease, digestive deseases NF-kappa Bdigestive disease, digestive deseases Protein Kinase Inhibitorsdigestive disease, digestive deseases Reverse Transcriptase Polymerase Chain Reactiondigestive disease, digestive deseases Signal Transductiondigestive disease, digestive deseases Sirolimusdigestive disease, digestive deseases Time Factorsdigestive disease, digestive deseases TOR Serine-Threonine Kinases

Abstract:

BACKGROUND & AIMS: Campylobacter jejuni is the worldwide leading cause of bacterial-induced enteritis. The molecular and cellular events that lead to campylobacteriosis are poorly understood. We identify mammalian target of rapamycin (mTOR) as a signaling pathway that leads to C jejuni-induced intestinal inflammation.

METHODS: Germ-free (control) or conventionally derived Il10(-/-) mice that express enhanced green fluorescent protein (EGFP) under the control of nuclear factor κB (Il10(-/-); NF-κB(EGFP) mice) were infected with C jejuni (10(9) colony-forming units/mouse) for 12 days; their responses were determined using histologic, semiquantitative reverse-transcription polymerase chain reaction, fluorescence in situ hybridization, transmission electron microscopy, and tissue culture analyses. mTOR signaling was blocked by daily intraperitoneal injections of the pharmacologic inhibitor rapamycin (1.5 mg/kg). CD4(+) T cells were depleted by intraperitoneal injections of antibodies against CD4 (0.5 mg/mouse every 3 days). Bacterial survival in splenocytes was measured using a gentamycin killing assay.

RESULTS: C jejuni induced intestinal inflammation, which correlated with activation of mTOR signaling and neutrophil infiltration. The inflamed intestines of these mice had increased levels of interleukin-1β, Cxcl2, interleukin-17a, and EGFP; C jejuni localized to colons and extraintestinal tissues of infected Il10(-/-); NF-κB(EGFP) mice compared with controls. Rapamycin, administered before or after introduction of C jejuni, blocked C jejuni-induced intestinal inflammation and bacterial accumulation. LC3II processing and killing of C jejuni were increased in splenocytes incubated with rapamycin compared with controls.

CONCLUSIONS: mTOR signaling mediates C jejuni-induced colitis in Il10(-/-) mice, independently of T-cell activation. Factors involved in mTOR signaling might be therapeutic targets for campylobacteriosis.