Biomedical Engineering Reference
In-Depth Information
airway distress syndrome model in piglets [155]. Finally,
in situ
delivery of PTD-
5-NBD was shown to improve pancreatic islet function and viability prior to trans-
plantation [156].
Other promising peptides that could be applied clinically are peptides blocking
interactions at other levels in the pathway. For example, a peptide corresponding to
amino acids 138-151 of mouse TIR domain-containing adaptor protein (TIRAP)
has been coupled with the antennapedia protein to facilitate uptake. This TIRAP-
fusion peptide blocked TIRAP's association with TLR4, resulting in inhibition of
LPS-induced NF-
B activation in macrophages [157]. An alternative strategy to
prevent IKK-activation has been described that is based on prevention of NEMO-
oligomerization by delivery of peptides encompassing the minimal oligomerization
domain of NEMO itself. These peptides were shown to inhibit NF-
κ
κ
B activation in
pre-B lymphocytes [158]. Another elegant way of inhibiting NF-
B is by application
of SN50, which is a fusion between a cell membrane-permeable motif (the hydro-
phobic domain of the signaling peptide) and a peptide corresponding to the nuclear
localization sequence (NLS) of p50. Application of this peptide in T cells not only
inhibits the nuclear translocation of NF-
κ
B but also the translocation of AP-1, NFAT,
and STAT1. The mechanism behind this inhibition is that SN50 interacts with and
binds to an NLS-receptor complex present in the cytoplasm of these cells [159
,
160].
Takade and colleagues described the coupling of the antennapedia membrane-trans-
port domain to a peptide encompassing a phosphorylation site of p65 whose phos-
phorylation is essential for NF-
κ
κ
B activity. This peptide was able to inhibit NF-
κ
B
signaling triggered by a range of stimuli [161].
The progress in DNA/RNA technology may provide new approaches to inhibit
NF-
B activity, e.g., by application of antisense oligodeoxynucleotides (ODNs),
ribozymes, decoy ODNs, and of course small interfering RNAs (siRNAs) [162
,
163].
Decoy ODNs are small DNA sequences carrying the consensus binding sequence
for specific transcription factors, in this case the
κ
κ
B site to which NF-
κ
B binds. In
a mouse model for asthma (ova-induced airway allergy),
κ
B-decoy oligos strongly
inhibited NF-
B activity, lung inflammation, airway hyperresponsiveness, and pro-
duction of mucus [164]. With the rapid advance in the small RNA field [163], its
potential to modify NF-
κ
B signaling is also beginning to be explored. Administration
of siRNA directed against p65 (siP65) was shown to enhance sensitivity to chemo-
therapeutic agents, such as irinotecan, and modified NF-
κ
κ
B-mediated inflammation
[165
,
166]. Various siRNA's against NF-
B mRNAs have already shown their inhib-
itory capacity
in vitro
[167
,
168]. Clearly, this will be an important therapeutic
modality, but it will require safe and efficacious delivery methods.
κ
10.6
OUTLOOK
At the dawn of twenty-first century, the advances in molecular biology and biochem-
istry have given investigators powerful new tools to study the molecular underpin-
nings of signaling pathways. The functions of IKKs (and several other kinases), so
central in NF-
B signaling, can now be studied in whole organism models like
Drosophila
[169-171] and zebrafish [172
,
173], which will facilitate the application
κ
