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PI3K p110β Positively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages and Dendritic Cells and JNK1 Plays a Novel Role¹

Mitsuyoshi Utsugi^2,*, Kunio Dobashi, Akihiro Ono^*, Tamotsu Ishizuka^*, Shin-ichi Matsuzaki^*, Takeshi Hisada^*, Yasuo Shimizu^*, Tadayoshi Kawata^*, Haruka Aoki^*, Yosuke Kamide^* and Masatomo Mori^*

^* Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan; and Gunma University School of Health Sciences, Maebashi, Japan

The PI3K family is thought to participate in TLR signaling, and it has been reported to be a negative regulator of TLR-mediated production of IL-12, a key inducer of Th1 responses. However, the role of individual PI3K subtypes in IL-12 production remains obscure. We defined the distinct regulation of LPS-mediated IL-12 production by p110 and p110β catalytic subunits of PI3K in human APCs. We observed that knockdown of PI3K p110β by small interfering RNA (siRNA) suppressed both LPS-induced IL-12 protein production and mRNA expression in monocyte-derived macrophages and dendritic cells (DCs). Knockdown of PI3K p110 by siRNA reduced LPS-induced IL-12 protein production in both cell types. Conversely, knockdown of PI3K p110 suppressed LPS-induced IL-12 mRNA expression in monocyte-derived macrophages but minimally affected monocyte-derived DCs. PI3K p110β siRNA inhibited JNK activation, but not p38 MAPK or ERK activation, stimulated by LPS, while PI3K p110 siRNA did not affect LPS-induced JNK, p38 MAPK, or ERK activation in both cell types. Transfection of siRNA against JNK1, JNK2, and both decreased LPS-induced IL-12 production. Furthermore, PI3K p110β siRNA attenuated LPS-induced JNK1 phosphorylation, while not affecting JNK2 phosphorylation. Our findings indicate that PI3K p110β positively controls LPS-induced IL-12 production through the JNK1-dependent pathway in human macrophages and DCs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grant 19790680 from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to M.U.).

² Address correspondence and reprint requests to Dr. Mitsuyoshi Utsugi, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail address: mutsugi{at}med.gunma-u.ac.jp

³ Abbreviations used in this paper: DC, dendritic cell; MD-DC, monocyte-derived DC; MD-macrophage, monocyte-derived macrophage; siRNA, small interfering RNA.

⁴ The online version of this article contains supplemental material.