Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.7.6 (
RNA polymerase
)
34,946
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
NF-kappaB repressing factor
(
NRF
), a nuclear inhibitor of NF-kappaB, is constitutively expressed and is implicated in the basal silencing of specific NF-kappaB targeting genes, including IFN-beta, IL-8/CXCL8, and iNOS. Little is known about the regulation of
NRF
and its role in response to stimuli. Airway smooth muscle (ASM) is a rich source of inflammatory mediators that may regulate the development and progression of airway inflammation. We have previously reported that NE activates NF-kappaB in primary human ASM (hASM), leading to induction of TGF-beta1. In this study, we describe that, instead of inducing the NF-kappaB response gene IL-8/CXCL8, NE suppressed IL-8/CXCL8 release and mRNA expression in hASM cells. Transcriptional blockade studies using actinomycin D revealed a similar degradation rate of IL-8/CXCL8 mRNA in the presence or absence of NE, suggesting an involvement at the transcription level. Mechanistically, the NE repressive effect was mediated by inducing
NRF
, as shown by RT-PCR and Western blotting, which was subsequently recruited to the native IL-8/CXCL8 promoter leading to removal of
RNA polymerase II
from the promoter, as demonstrated by chromatin immunoprecipitation assays. Knockdown of
NRF
by small interfering RNA prevented NE-induced suppression of IL-8/CXCL8 expression. In contrast, NE did not induce
NRF
expression in A549 and Beas-2B cells, where NE only stimulates NF-kappaB activation and IL-8/CXCL8 induction. Forced expression of
NRF
in A549 cells by an
NRF
expression plasmid suppressed IL-8/CXCL8 expression. Hence, we describe a novel negative regulatory mechanism of NE-induced
NRF
, which is restricted to hASM and mediates the suppression of IL-8/CXCL8 expression.
...
PMID:Neutrophil elastase represses IL-8/CXCL8 synthesis in human airway smooth muscle cells through induction of NF-kappa B repressing factor. 1954 52
