Coinduction of inducible nitric oxide synthase and arginine recycling enzymes in cytokine-stimulated PC12 cells and high output production of nitric oxide

Brain Res Mol Brain Res. 2000 Nov 10;83(1-2):1-8. doi: 10.1016/s0169-328x(00)00154-6.

Abstract

Nitric oxide (NO) is involved in many physiological and pathological processes in the brain. NO is synthesized from arginine by nitric oxide synthase (NOS), and the citrulline generated as a by-product can be recycled to arginine by argininosuccinate synthetase (AS) and argininosuccinate lyase (AL) via the citrulline-NO cycle. When neuronal PC12 cells differentiated with nerve growth factor were treated with interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha), iNOS and AS mRNAs and proteins were markedly induced, with AL mRNA and protein being weakly induced. Cationic amino acid transporter-1 and -2 were not induced. IFNgamma or TNFalpha alone was ineffective. A large amount of NO (190 microM NO(2)(-) plus NO(3)(-) in culture medium in 24 h) was produced from arginine by cytokine-stimulated cells, and arginine could be replaced by citrulline. iNOS induction and NO production were attenuated by dexamethasone and dibutyryl cAMP and even more strongly so when combined. Therefore, a large amount of NO is produced in cytokine-stimulated PC12 cells following to induction of iNOS and citrulline-arginine recycling is important for NO production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Arginine / metabolism*
  • Argininosuccinate Lyase / metabolism
  • Argininosuccinate Synthase / metabolism
  • Bucladesine / pharmacology
  • Citrulline / metabolism
  • Dexamethasone / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glucocorticoids / pharmacology
  • Interferon-gamma / pharmacology
  • Lipopolysaccharides / pharmacology
  • Nerve Growth Factor / pharmacology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / genetics*
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • PC12 Cells
  • RNA, Messenger / analysis
  • Rats
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Antineoplastic Agents
  • Glucocorticoids
  • Lipopolysaccharides
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Citrulline
  • Nitric Oxide
  • Bucladesine
  • Dexamethasone
  • Interferon-gamma
  • Nerve Growth Factor
  • Arginine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Argininosuccinate Lyase
  • Argininosuccinate Synthase