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Critical Roles of the p110β Subtype of Phosphoinositide 3-Kinase in Lipopolysaccharide-Induced Akt Activation and Negative Regulation of Nitrite Production in RAW 264.7 Cells

Ken Tsukamoto^*, Kaoru Hazeki^1,*, Megumi Hoshi^*, Kiyomi Nigorikawa^*, Norimitsu Inoue, Takehiko Sasaki and Osamu Hazeki^*

^* Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; and Department of Pathology and Immunology, Akita University School of Medicine, Akita, Japan

It has been suggested that PI3K participates in TLR signaling. However, identifying specific roles for individual PI3K subtypes in signaling has remained elusive. In macrophages from the p110^–/– mouse, LPS-induced phosphorylation of Akt occurred normally despite the fact that the action of anaphylatoxin C5a was impaired markedly. In RAW 264.7 cells expressing short hairpin RNA that targets p110β, LPS-induced phosphorylation of Akt was significantly attenuated. In contrast, the LPS action was not impaired, but was rather augmented in the p110-deficient cells. Previous pharmacologic studies have suggested that a PI3K-Akt pathway negatively regulates TLR-induced inducible NO synthase expression and cytokine production. In the p110β-deficient cells, inducible NO synthase expression and IL-12 production upon stimulation by LPS were increased, whereas LPS-induced expression of COX-2 and activation of MAPKs were unaffected. Together, the results suggest a specific function of p110β in the negative feedback regulation of TLR signaling.

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¹ Address correspondence and reprint requests to Dr. Kaoru Hazeki, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan. E-mail address: khazeki{at}hiroshima-u.ac.jp

² Abbreviations used in this paper: TIR, Toll-IL-1R; GSK, glycogen synthase kinase; COX, cyclooxygenase; poly(I:C), polyinosinic-polycytidylic acid; IKK, IB kinase; iNOS, inducible NO synthase; Malp, macrophage-activating lipopeptide; PTX, pertussis toxin; shRNA, short hairpin RNA.