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First published on February 10, 2006; DOI: 10.1124/mol.105.021162

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Received for publication November 30, 2005.
Revised February 9, 2006.
Accepted for publication February 10, 2006.

Opposite effects of wortmannin and LY294002 on TLR- mediated nitric oxide production: negative regulation of NF-{kappa}B by phosphoinositide 3-kinase

Kaoru Hazeki 1*, Sachiko Kinoshita 2, Takayo Matsumura 1, Kiyomi Nigorikawa 1, Hiroshi Kubo 1, Osamu Hazeki 1

1 Hiroshima University 2 Hiroshima university

* Address correspondence to: E-mail: khazeki{at}hiroshima-u.ac.jp

Abstract

A number of previous studies have suggested the involvement of phosphoinositide 3-kinase (PI3K) in 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 NF-{kappa}B and up- regulation of cytokine mRNA production. Surprisingly, another PI3K inhibitor, LY294002, strongly suppressed the production of iNOS and cytokines. This effect of LY294002 was based on its inhibitory effect on mRNA synthesis. Expression of dominant negative mutants of PI3K in macrophages augmented the LPS-induced expression of iNOS. Introduction of a pH1 vector producing short hairpin RNA (shRNA) that targets a catalytic subunit of PI3K (p110{beta}) also enhanced the TLR-mediated responses. Thus, the augmentation of TLR signals by wortmannin was mediated through inhibition of PI3K, while 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.


Key words: Nitric oxide synthases, Interleukins, NFkappaB


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