Phosphoinositide 3-kinase in nitric oxide synthesis in macrophage: Critical dimerization of inducible nitric-oxide synthase

Kouhei Sakai, Harumi Suzuki, Hiroyo Oda, Takaaki Akaike, Yoshinao Azuma, Tomoyuki Murakami, Kazuro Sugi, Takehito Ito, Hiroshi Ichinose, Shigeo Koyasu, Mutsunori Shirai

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


Phosphoinositide 3-kinase (PI3K) has important functions in various biological systems, including immune response. Although the role of PI3K in signaling by antigen-specific receptors of the adaptive immune system has been extensively studied, less is known about the function of PI3K in innate immunity. In the present study, we demonstrate that macrophages deficient for PI3K (p85α regulatory subunit) are impaired in nitric oxide (NO) production upon lipopolysaccharide and interferon-γ stimulation and thus vulnerable for intracellular bacterial infection such as Chlamydophila pneumoniae. Although expression of inducible nitric-oxide synthase (iNOS) is induced normally in PI3K-deficient macrophages, dimer formation of iNOS protein is significantly impaired. The amount of intracellular tetrahydrobiopterin, a critical stabilizing cofactor for iNOS dimerization, is decreased in the absence of PI3K. In addition, induction of GTP cyclohydrolase 1, a rate-limiting enzyme for biosynthesis of tetrahydrobiopterin, is greatly reduced. Our current results demonstrate a critical role of class IA type PI3K in the bactericidal activity of macrophages by regulating their NO production through GTP cyclohydrolase 1 induction.

Original languageEnglish
Pages (from-to)17736-17742
Number of pages7
JournalJournal of Biological Chemistry
Issue number26
Publication statusPublished - 2006 Jun 30
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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