Unknown,Transcriptomics,Genomics,Proteomics

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Developmental LTbR synergistically activates TLR4 mediated inflammatory RelA/NF-kB response


ABSTRACT: Developmental signals are known to modulate inflammation. How ever, the mechanistic insight that links developmental and inflammatory signaling remains elusive. In the current study, we identifya critical role of NF-kB system in mediating stimulus specific crosstalk that allows developmental LTbR signals to sustain inflammatory TLR4 induced RelA/NF-kB response and gene expression. LTbR activated non-canonical signaling targets canonical TLR4 induced, nfkb2 encoded p100 not only to deplete inhibitory IkBd/(p100)2, but also to supplement RelA:p52/NF-kB dimers. Robust crosstalk in the gut epithelial cells are important, as crosstalk-defective nfkb2-/- mice succumbed to gut infection by Citrobacter rodentium due to hypo-inflammatory responses. Finally, we present evidence for a crosstalk motif that integrates tissue microenvironment derived developmental cues to ameliorate the pathogen response. Total RNA from WT early passage MEFs stimulated with ligands LPS, LTbR and LPS+LTbR for 24hrs were analyzed for global gene expression levels

ORGANISM(S): Mus musculus

SUBMITTER: Balaji Banoth 

PROVIDER: E-GEOD-62301 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Stimulus-selective crosstalk via the NF-κB signaling system reinforces innate immune response to alleviate gut infection.

Banoth Balaji B   Chatterjee Budhaditya B   Vijayaragavan Bharath B   Prasad M V R MV   Roy Payel P   Basak Soumen S  

eLife 20150423


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-  ...[more]

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