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

The Journal of Biological Chemistry
Kouhei SakaiMutsunori Shirai

Abstract

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 (p85alpha regulatory subunit) are impaired in nitric oxide (NO) production upon lipopolysaccharide and interferon-gamma 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.

References

Jan 1, 1985·Annual Review of Biochemistry·C A NicholD S Duch
Feb 1, 1980·Analytical Biochemistry·T Fukushima, J C Nixon
Dec 8, 1995·The Journal of Biological Chemistry·R S LewisW M Deen
Jan 17, 1995·Biochemical and Biophysical Research Communications·I M CorralizaM Modolell
Sep 14, 1994·Journal of Immunological Methods·I M CorralizaM Modolell
Jan 1, 1995·Journal of Neural Transmission. General Section·I NagatsuT Nagatsu
Apr 7, 1998·Infection and Immunity·J U IgietsemeH D Caldwell
Jun 24, 1998·Proceedings of the National Academy of Sciences of the United States of America·N T EissaJ Moss
Jan 5, 1999·The Journal of Biological Chemistry·E A RatovitskiC J Lowenstein
May 13, 1999·Biochimica Et Biophysica Acta·D J Stuehr
May 25, 1999·Infection and Immunity·H MatsushimaT Nakazawa
Jul 10, 1999·The Journal of Biological Chemistry·Y HayashiY Watanabe
Oct 9, 1999·The Journal of Biological Chemistry·E A RatovitskiC J Lowenstein
Jun 8, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·C D MillsA M Hill
Feb 13, 2001·The International Journal of Biochemistry & Cell Biology·M IshiiT Yamamoto
Mar 20, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·M M MonickG W Hunninghake
Mar 30, 2001·The Journal of Biological Chemistry·B NicholsonC L MacLeod
Mar 30, 2001·The Journal of Biological Chemistry·D StuehrG M Rosen
Jul 21, 2001·The Biochemical Journal·W K AldertonR G Knowles
Nov 21, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·A G RothfuchsM E Rottenberg
Mar 21, 2002·Proceedings of the National Academy of Sciences of the United States of America·Jin HuangBernhard Kaltenboeck
Aug 3, 2002·Nature Immunology·Taro FukaoShigeo Koyasu
Sep 11, 2002·Proceedings of the National Academy of Sciences of the United States of America·Pawel J KolodziejskiN Tony Eissa

❮ Previous
Next ❯

Citations

Jul 31, 2013·Mycotoxin Research·Kei-ichi SugiyamaYoshiko Sugita-Konishi
Mar 25, 2009·The Journal of Pharmacology and Experimental Therapeutics·Galen M PieperJeannette Vásquez-Vivar
Oct 7, 2008·American Journal of Physiology. Heart and Circulatory Physiology·Irina A IonovaGalen M Pieper
Oct 29, 2013·Microbes and Infection·Muthusamy V ShanmuganathanNemani V Prasadarao
Sep 18, 2010·The American Journal of Pathology·Liye ChenShijie Cai
Aug 27, 2013·Journal of Immunotoxicology·Wioletta Ratajczak-WronaKamil Grubczak
May 27, 2011·Critical Care : the Official Journal of the Critical Care Forum·Andrea PolitoTarek Sharshar
May 21, 2016·Frontiers in Immunology·Fabiane SônegoFernando Queiróz Cunha
Mar 1, 2017·Journal of Cellular and Molecular Medicine·Xiao-Fei ShenJun-Feng Du
Oct 28, 2017·International Journal of Molecular Sciences·Byungki JangEun-Kyoung Choi
Jan 25, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Eleni VergadiChristos Tsatsanis
May 29, 2014·Expert Review of Clinical Immunology·Fabiane SônegoFernando Queiróz Cunha
Apr 2, 2021·The Journal of Pharmacy and Pharmacology·Cynthia Maria C PereiraAndré Luiz Reis Barbosa

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.