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

Author:
Park, Sung-Dong, Cheon, So Yeong, Park, Tae-Yoon, Shin, Bo-Young, Oh, Hyunju, Ghosh, Sankar, Koo, Bon-Nyeo, Lee, Sang-Kyou
Source:
Biochemical and biophysical research communications 2015 v.464 pp. 711-717
ISSN:
0006-291X
Subject:
T-lymphocytes, adaptive immunity, cell viability, interferon-gamma, interleukin-10, interleukin-17, interleukin-1beta, interleukin-2, interleukin-4, interleukin-6, lipopolysaccharides, mitogen-activated protein kinase, models, neuroglia, pathogenesis, phosphorylation, secretion, sepsis (infection), therapeutics, transcription (genetics), transcription factor NF-kappa B, tumor necrosis factor-alpha, tyrosine
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.
Agid:
5332196