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Rac1 Negatively Regulates Lipopolysaccharide-Induced IL-23 p19 Expression in Human Macrophages and Dendritic Cells and NF-B p65 trans Activation Plays a Novel Role¹

Mitsuyoshi Utsugi^2,*, Kunio Dobashi, Tamotsu Ishizuka^*, Tadayoshi Kawata^*, Takeshi Hisada^*, Yasuo Shimizu^*, Akihiro Ono^* and Masatomo Mori^*

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

IL-23 is a heterodimeric cytokine composed of a unique p19 subunit and of a p40 subunit that is also common to IL-12. We defined the distinct signaling mechanisms that regulate the LPS-mediated induction of IL-23 p19 and p40 in human macrophages and dendritic cells. We found that the overexpression of dominant-negative Rac1 (N17Rac1) enhanced LPS-induced IL-23 p19 expression but did not alter p40 expression or IL-12 p70 production in PMA-treated THP-1 macrophages and in human monocyte-derived dendritic cells. Although the inhibition of either p38 MAPK or JNK enhanced LPS-induced p19 expression, N17Rac1 did not influence either p38 MAPK or JNK activation. By contrast, N17Rac1 augmented both NF-B gene expression and p65 trans activation stimulated by LPS without affecting the degradation of IB- or DNA binding to NF-B. Furthermore, small interference RNA of NF-B p65 attenuated cellular amounts of p65 and suppressed LPS-induced p19 expression but did not affect p40 expression. Our findings indicate that Rac1 negatively controls LPS-induced IL-23 p19 expression through an NF-B p65 trans activation-dependent, IB-independent pathway and that NF-B p65 regulates LPS-induced IL-23 p19, but not p40, expression, which causes differences in the control of IL-23 p19 and p40 expression by Rac1.

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 17790667 (to M.U.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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: PRR, pattern recognition receptor; DC, dendritic cell; EGFP, enhanced GFP; MD-DC, monocyte-derived DC; N17Rac1 fragment, dominant-negative Rac1 fragment; Ad.N17Rac1, adenovirus harboring N17Rac1; Ad.EGFP, control adenovirus; siRNA, small interference RNA.

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