scholarly journals Functional analysis of the interleukin-1-receptor-associated kinase (IRAK-1) in interleukin-1β-stimulated nuclear factor κB (NF-κB) pathway activation: IRAK-1 associates with the NF-κB essential modulator (NEMO) upon receptor stimulation

2001 ◽  
Vol 359 (2) ◽  
pp. 403 ◽  
Author(s):  
Emma-Louise COOKE ◽  
Iain J. UINGS ◽  
Chulin L. XIA ◽  
Patricia WOO ◽  
Keith P. RAY
Keyword(s):  
Functional Analysis ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Interleukin 1Β ◽  
Nuclear Factor ◽  
Receptor Stimulation ◽  
Pathway Activation

Functional analysis of the interleukin-1-receptor-associated kinase (IRAK-1) in interleukin-1β-stimulated nuclear factor κB (NF-κB) pathway activation: IRAK-1 associates with the NF-κB essential modulator (NEMO) upon receptor stimulation

2001 ◽  
Vol 359 (2) ◽  
pp. 403-410 ◽  
Author(s):  
Emma-Louise COOKE ◽  
Iain J. UINGS ◽  
Chulin L. XIA ◽  
Patricia WOO ◽  
Keith P. RAY
Keyword(s):  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Full Length ◽  
Nuclear Factor ◽  
Terminal Domain ◽  
Iκb Kinase ◽  
C Terminus ◽  
Pathway Activation ◽  
Cytokine Stimulation ◽  
Factor Α

The interleukin-1 (IL-1)-receptor-associated kinase (IRAK-1) is essential for IL-1-stimulated nuclear factor κB (NF-κB) activation. To study the role of IRAK-1 in IL-1β signalling, we have generated a set of IRAK-1 variants that express distinct domains of IRAK-1 either alone or in combination and have examined their effects on an NF-κB-responsive reporter in HeLa cells. Unlike full-length IRAK-1, the deletion mutants were unable to activate NF-κB in the absence of cytokine stimulation. However, an IRAK-1 variant lacking only the N-terminal domain retained the ability of the full-length protein to potentiate both IL-1β and tumour necrosis factor α (TNFα)-induced NF-κB activation. In contrast, expression of the N-terminus or the C-terminus of IRAK-1, or a fusion protein incorporating both domains, inhibited both IL-1β- and TNFα-induced effects. Expression of an IRAK-1 variant lacking only the C-terminal domain preferentially inhibited IL-1β versus TNFα-induced NF-κB activation. These data suggest that the C-terminal domain may link IRAK-1 to downstream signalling components common to both the IL-1 and TNF pathways. Furthermore, we have demonstrated that endogenous IRAK-1 becomes phosphorylated upon IL-1β treatment and can be detected along with NF-κB essential modulator (NEMO) and IκB kinase β (IKKβ) in high-molecular-mass complexes of 600–800kDa. Moreover, IRAK-1 could be detected in NEMO immunoprecipitates from IL-1β-stimulated cells. We conclude that IRAK-1 mediates IL-1β signal transduction through a ligand-dependent association of IRAK-1 with the IKK complex.

scholarly journals A novel splice variant of mouse interleukin-1-receptor-associated kinase-1 (IRAK-1) activates nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)

2003 ◽  
Vol 370 (1) ◽  
pp. 159-166 ◽  
Author(s):  
Ken YANAGISAWA ◽  
Kenji TAGO ◽  
Morisada HAYAKAWA ◽  
Motomichi OHKI ◽  
Hiroyuki IWAHANA ◽  
...  
Keyword(s):  
Splice Variant ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Acceptor Site ◽  
Nuclear Factor ◽  
Death Domain ◽  
Signalling Molecule ◽  
Novel Variant ◽  
Nf Kappab

Interleukin-1 (IL-1)-receptor-associated kinase (IRAK) is an indispensable signalling molecule for host-defence responses initiated by a variety of ligands that bind to members of the Toll/IL-1 receptor family. Here we report a novel splice variant of mouse IRAK-1, IRAK-1-S, which is generated by utilizing a new splicing acceptor site within exon 12. IRAK-1-S cDNA is shorter than the originally reported IRAK-1 (IRAK-1-W) cDNA by 271 nucleotides, and the subsequent frameshift causes a premature termination of translation after 23 amino acids, which are unique to the IRAK-1-S protein. To elucidate the physiological function of IRAK-1-S, we overexpressed it in 293T cells and studied the effects on the IL-1 signalling cascade. As it lacks the C-terminal region of IRAK-1-W that has been reported to contain the TRAF6 (tumour necrosis factor receptor-associated factor 6) binding domain, IRAK-1-S was unable to bind TRAF6 protein, which is a proposed downstream signalling molecule. However, IRAK-1-S overexpressed in 293T cells induced constitutive activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) independent of stimulation by IL-1, as did IRAK-1-W. To clarify the mechanism of NF-κB activation by IRAK-1-S in the absence of binding to TRAF6, we demonstrated that IRAK-1-S binds to IRAK-1-W through its death domain; the findings suggested that overexpressed IRAK-1-S may bind endogenous IRAK-1-W and activate TRAF6 through IRAK-1-W. These results also indicate that this novel variant may play roles in the activation of NF-κB and JNK by IL-1 and other ligands whose signal transduction is dependent on IRAK-1 under physiological conditions.

Is the Effect of Interleukin-1 on Glutathione Oxidation in Cultured Human Fibroblasts Involved in Nuclear Factor-κB Activation?

2001 ◽  
Vol 3 (2) ◽  
pp. 329-340 ◽  
Author(s):  
Patricia Renard ◽  
Edouard Delaive ◽  
Martine Van Steenbrugge ◽  
José Remacle ◽  
Martine Raes
Keyword(s):  
Interleukin 1 ◽  
Human Fibroblasts ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Cultured Human Fibroblasts ◽  
Glutathione Oxidation

Role of nuclear factor-κB in gastric ulcer healing in rats

2001 ◽  
Vol 280 (6) ◽  
pp. G1296-G1304 ◽  
Author(s):  
Satoru Takahashi ◽  
Takuya Fujita ◽  
Akira Yamamoto
Keyword(s):  
Gastric Ulcer ◽  
Mrna Expression ◽  
Ulcer Healing ◽  
Nuclear Factor Κb ◽  
Normal Mucosa ◽  
Cyclooxygenase 2 ◽  
Interleukin 1Β ◽  
Nuclear Factor ◽  
Gastric Ulcer Healing

We investigated the role of nuclear factor-κB (NF-κB) in gastric ulcer healing in rats. NF-κB was activated in ulcerated tissue but not in normal mucosa, and the level of the activation was decreased with ulcer healing. NF-κB activation was observed in fibroblasts, monocytes/macrophages, and neutrophils. Treatment of gastric fibroblasts, isolated from the ulcer base, with interleukin-1β activated NF-κB and the subsequently induced cyclooxygenase-2 and cytokine-induced neutrophil chemoattractant-1 (CINC-1) mRNA expression. Inhibition of activated NF-κB action resulted in suppression of both their mRNA expression and increases in PGE2 and CINC-1 levels induced by interleukin-1β. Persistent prevention of NF-κB activation caused an impairment of ulcer healing in rats. Gene expression of interleukin-1β, CINC-1, cyclooxygenase-2, and inducible nitric oxide synthase in ulcerated tissue had been inhibited before the delay in ulcer healing became manifest. The increased levels of cyclooxygenase-2 protein and PGE2 production were also reduced. These results demonstrate that NF-κB, activated in ulcerated tissue, might upregulate the expression of healing-promoting factors responsible for gastric ulcer healing in rats.

Acetaminophen down-regulates interleukin-1β-induced nuclear factor-κB nuclear translocation in a human astrocytic cell line

2003 ◽  
Vol 353 (2) ◽  
pp. 79-82 ◽  
Author(s):  
Francesca Mancini ◽  
Carla Landolfi ◽  
Marta Muzio ◽  
Luciano Aquilini ◽  
Lucia Soldo ◽  
...  
Keyword(s):  
Cell Line ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Interleukin 1Β ◽  
Nuclear Factor

scholarly journals Predictive Value of Nuclear Factor κB Activity and Plasma Cytokine Levels in Patients with Sepsis

2000 ◽  
Vol 68 (4) ◽  
pp. 1942-1945 ◽  
Author(s):  
Francisco Arnalich ◽  
Esther Garcia-Palomero ◽  
Julia López ◽  
Manuel Jiménez ◽  
Rosario Madero ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Regulatory Protein ◽  
Nuclear Factor Κb ◽  
Apache Ii Score ◽  
Nuclear Factor ◽  
Early Measurement ◽  
Peripheral Blood Mononuclear ◽  
Cytokine Levels

ABSTRACT The relationship between fluctuating cytokine concentrations in plasma and the outcome of sepsis is complex. We postulated that early measurement of the activation of nuclear factor κB (NF-κB), a transcriptional regulatory protein involved in proinflammatory cytokine expression, may help to predict the outcome of sepsis. We determined NF-κB activation in peripheral blood mononuclear cells of 34 patients with severe sepsis (23 survivors and 11 nonsurvivors) and serial concentrations of inflammatory cytokines (interleukin-6, interleukin-1, and tumor necrosis factor) and various endogenous antagonists in plasma. NF-κB activity was significantly higher in nonsurvivors and correlated strongly with the severity of illness (APACHE II score), although neither was related to the cytokine levels. Apart from NF-κB activity, the interleukin-1 receptor antagonist was the only cytokine tested whose level in plasma was of value in predicting mortality by logistic regression analysis. These results underscore the prognostic value of early measurement of NF-κB activity in patients with severe sepsis.

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