HUMAN INTERLEUKIN-1 RECEPTOR ASSOCIATED KINASE-2 (IRAK-2) IS ESSENTIAL FOR TOLL-LIKE RECEPTOR-MEDIATED TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION OF TNFα
Citation:
Sinead M. Flannery, Sinead E. Keating, Joanna Syzmak and Andrew G. Bowie, HUMAN INTERLEUKIN-1 RECEPTOR ASSOCIATED KINASE-2 (IRAK-2) IS ESSENTIAL FOR TOLL-LIKE RECEPTOR-MEDIATED TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION OF TNFα, Journal of Biological Chemistry, 286, 2011, 23688 - 23697Download Item:
Abstract:
Toll-like receptors (TLRs) are pattern
recognition receptors that recognise microbial
ligands and subsequently trigger intracellular
signalling pathways involving transcription
factors such as NF?B and MAPKs such as
p38. TLR signalling can regulate both
transcriptional and post-transcriptional
events leading to altered gene expression, and
thus appropriate immune responses. The
interleukin-1 receptor associated kinase
(IRAK) family comprises four kinases that
regulate TLR signalling. However, the role of
IRAK-2 has remained unclear, especially in
human cells. Recent studies using cells from
in-bred IRAK-2-/- mice showed that murine
IRAK-2 was not required for early TLR
signalling events, but had a role in delayed
NF?B activation and in cytokine production.
IRAK-2 in mice has four splice variants, two
of which are inhibitory, while human IRAK-2
has no splice variants. Thus IRAK-2 in mice
and humans may function differently, and
therefore we analyzed of the role of IRAK-2
in TLR responses in primary human cells.
SiRNA knockdown of IRAK-2 expression in
human peripheral blood mononuclear cells
showed a role for human IRAK-2 in both
TLR4 and TLR8-mediated early NF?B and
p38 MAP kinase activation, and in induction
of TNF mRNA. These data conflict with
findings from the in-bred IRAK2-/- mice, but
concur with what has been seen in wildderived
mice for TLR2. Moreover, human
IRAK-2 was required for regulating MyD88-
dependent TNF? mRNA stability via the TNF
3?UTR. Collectively these data demonstrate
for the first time an essential role for IRAK-2
in primary human cells for both
transcriptional and post-transcriptional TLR
responses.
Sponsor
Grant Number
Science Foundation Ireland (SFI)
Health Research Board (HRB)
Author's Homepage:
http://people.tcd.ie/agbowieDescription:
PUBLISHEDPubMed ID: 21606490
Author: BOWIE, ANDREW
Sponsor:
Science Foundation Ireland (SFI)Health Research Board (HRB)
Type of material:
Journal ArticleCollections
Series/Report no:
Journal of Biological Chemistry286
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Toll-like receptors (TLRs)Subject (TCD):
Immunology, Inflammation & InfectionDOI:
http://dx.doi.org/10.1074/jbc.M111.248351Metadata
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