Stimulus-selective crosstalk via the NF-κB signaling system reinforces innate immune response to alleviate gut infection.
Elife
; 42015 Apr 23.
Article
en En
| MEDLINE
| ID: mdl-25905673
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-ß receptor (LTßR) induced non-canonical NF-κB signaling. Indeed, LTßR costimulation synergistically enhanced the late RelA/NF-κB response to TLR4 prolonging NF-κB target gene-expressions. Concomitant LTßR 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
FN-kappa B
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Citrobacter rodentium
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Infecciones por Enterobacteriaceae
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Inmunidad Innata
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Inflamación
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Elife
Año:
2015
Tipo del documento:
Article
País de afiliación:
India
Pais de publicación:
Reino Unido