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

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 ofmore » 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. - Highlights: • The nt-p65-TMD is intra-nuclear interactomic inhibitor of endogenous p65. • The nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines. • The excellent therapeutic potential of nt-p65-TMD was confirmed in sepsis model.« less
Authors:
 [1] ;  [2] ;  [3] ; ;  [1] ;  [2] ; ;  [4] ;  [3] ;  [1] ;  [2]
  1. Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)
  2. (Korea, Republic of)
  3. Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of)
  4. Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States)
Publication Date:
OSTI Identifier:
22462220
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 464; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DISEASES; INFLAMMATION; INHIBITION; LYMPHOKINES; PATHOGENESIS; PHOSPHORYLATION; RECEPTORS; SECRETION; SIGNALS; STIMULATION; TRANSCRIPTION; TRANSCRIPTION FACTORS; TYROSINE; VIABILITY