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Intranuclear interactomic inhibition of NF-κB suppresses LPS-induced severe sepsis

Authors
 Sung-Dong Park  ;  So Yeong Cheon  ;  Tae-Yoon Park  ;  Bo-Young Shin  ;  Hyunju Oh  ;  Sankar Ghosh  ;  Bon-Nyeo Koo  ;  Sang-Kyou Lee 
Citation
 Biochemical and Biophysical Research Communications, Vol.464(3) : 711-717, 2015 
Journal Title
 Biochemical and Biophysical Research Communications 
ISSN
 0006-291X 
Issue Date
2015
Abstract
Suppression of nuclear factor-κB (NF-κB) activation, which is best known as a major regulator of innate and adaptive immune responses, is a potent strategy for the treatment of endotoxic sepsis. To inhibit NF-κB functions, we designed the intra-nuclear transducible form of transcription modulation domain (TMD) of RelA (p65), called nt-p65-TMD, which can be delivered effectively into the nucleus without influencing the cell viability, and work as interactomic inhibitors via disruption of the endogenous p65-mediated transcription complex. nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, or IL-6 from BV2 microglia cells stimulated by lipopolysaccharide (LPS). nt-p65-TMD did not inhibit tyrosine phosphorylation of signaling mediators such as ZAP-70, p38, JNK, or ERK involved in T cell activation, but was capable of suppressing the transcriptional activity of NF-κB without the functional effect on that of NFAT upon T-cell receptor (TCR) stimulation. The transduced nt-p65-TMD in T cell did not affect the expression of CD69, however significantly inhibited the secretion of T cell-specific cytokines such as IL-2, IFN-γ, IL-4, IL-17A, or IL-10. Systemic administration of nt-p65-TMD showed a significant therapeutic effect on LPS-induced sepsis model by inhibiting pro-inflammatory cytokines secretion. Therefore, nt-p65-TMD can be a novel therapeutics for the treatment of various inflammatory diseases, including sepsis, where a transcription factor has a key role in pathogenesis, and further allows us to discover new functions of p65 under normal physiological condition without genetic alteration.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140948
Full Text
http://www.sciencedirect.com/science/article/pii/S0006291X15302400
DOI
10.1016/j.bbrc.2015.07.008
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실)
Yonsei Authors
구본녀(Ku, Bon Nyo)
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