Details
- Autor(en) / Beteiligte
- Titel
- Stimulus-selective crosstalk via the NF-κB signaling system reinforces innate immune response to alleviate gut infection
- Ist Teil von
- eLife, 2015-04, Vol.4
- Ort / Verlag
- England: eLife Sciences Publications Ltd
- Erscheinungsjahr
- 2015
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Tissue microenvironment functions as an important determinant of the inflammatory response elicited by the resident cells. Yet, the underlying molecular mechanisms remain obscure. Our systems-level analyses identified a duration code that instructs stimulus specific crosstalk between TLR4-activated canonical NF-κB pathway and lymphotoxin-β receptor (LTβR) induced non-canonical NF-κB signaling. Indeed, LTβR costimulation synergistically enhanced the late RelA/NF-κB response to TLR4 prolonging NF-κB target gene-expressions. Concomitant LTβR signal targeted TLR4-induced newly synthesized p100, encoded by Nfkb2, for processing into p52 that not only neutralized p100 mediated inhibitions, but potently generated RelA:p52/NF-κB activity in a positive feedback loop. Finally, Nfkb2 connected lymphotoxin signal within the intestinal niche in reinforcing epithelial innate inflammatory RelA/NF-κB response to Citrobacter rodentium infection, while Nfkb2(-/-) mice succumbed to gut infections owing to stromal defects. In sum, our results suggest that signal integration via the pleiotropic NF-κB system enables tissue microenvironment derived cues in calibrating physiological responses.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2050-084XeISSN: 2050-084XDOI: 10.7554/eLife.05648Titel-ID: cdi_doaj_primary_oai_doaj_org_article_d15337698fc640f9b199dc9ff4c4f273
- Format
- –
- Schlagworte
- Animals, Chemokines, Citrobacter rodentium, Citrobacter rodentium - immunology, Citrobacter rodentium - pathogenicity, Computational and Systems Biology, Digestive system, Digestive tract, Enterobacteriaceae Infections - immunology, Feedback, Gene expression, Gene Expression Regulation - immunology, Immune response, Immunity, Innate - genetics, Immunology, Infections, Inflammation, Inflammation - genetics, Innate immunity, Intestinal Mucosa - immunology, Intestinal Mucosa - microbiology, Intestine, Kinases, Lymphotoxin, Lymphotoxin beta Receptor - genetics, Lymphotoxin beta Receptor - immunology, Mathematical models, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular modelling, Muridae, NF-kappa B - genetics, NF-kappa B - immunology, NF-kappa B p52 Subunit - deficiency, NF-kappa B p52 Subunit - genetics, NF-κB protein, Pathogens, Phosphorylation, positive feedback, RelA protein, RelA:p52/NF-kappaB, Signal Transduction - genetics, TLR4 protein, Toll-like receptors, Transcription Factor RelA - genetics, Transcription Factor RelA - immunology