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Hazeki K, Kinoshita S,
Matsumura T, Nigorikawa K, Kubo H, Hazeki O.
Opposite effects of wortmannin and
2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
on toll-like receptor-mediated nitric oxide production: negative
regulation of nuclear factor-{kappa}B by phosphoinositide
3-kinase.
Mol Pharmacol. 2006 May;69(5):1717-24.
A number of previous studies have suggested the involvement
of phosphoinositide 3-kinase (PI3K) in Toll-like receptor (TLR)
signaling. However, there have also been a number of conflicting
reports. The PI3K inhibitor wortmannin greatly enhanced TLR-mediated
inducible nitric-oxide synthase (iNOS) expression and cytokine
production in the mouse macrophage cell line Raw264.7. The
effect of wortmannin was common to TLR2, -3, -4, and -9 and was
accompanied by activation of nuclear factor-kappaB and
up-regulation of cytokine mRNA production. We were surprised to
find that another PI3K inhibitor, LY294002, strongly suppressed
the production of iNOS and cytokines. This effect of
2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
(LY294002) was based on its inhibitory effect on mRNA synthesis.
Expression of dominant-negative mutants of PI3K in macrophages
augmented the lipopolysaccharideinduced expression of iNOS.
Introduction of a pH1 vector producing short hairpin RNA that
targets a catalytic subunit of PI3K (p110beta) also enhanced the
TLR-mediated responses. Thus, the augmentation of TLR signals by
wortmannin was mediated through the inhibition of PI3K, whereas
the effect of LY294002 was not explained by its effect on PI3K.
These discrepancies in the effects of pharmacological inhibitors
in TLR-signaling may have caused confusion regarding the role of
PI3K in innate immunity.
PMID: 16474002
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