Pyrrolidine dithiocarbamate differentially affects interleukin 1 beta- and cAMP-induced nitric oxide synthase expression in rat renal mesangial cells

Biochem Biophys Res Commun. 1994 Apr 15;200(1):163-70. doi: 10.1006/bbrc.1994.1429.

Abstract

Inducible nitric oxide synthase (NOS) is expressed in renal mesangial cells in response to two principal classes of activating signals that interact in a synergistic fashion. These two groups of activators comprise inflammatory cytokines such as interleukin 1 (IL-1) or tumour necrosis factor alpha and agents that elevate cellular levels of cAMP. We have used pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of nuclear factor kappa B (NF kappa B), to determine its role in IL-1 beta- and cAMP-triggered NOS expression. Micromolar amounts of PDTC suppress IL-1 beta-, but not cAMP-stimulated nitrite production, the stable end product of NO formation in mesangial cells. Furthermore, PDTC completely inhibited the increase of NOS mRNA in response to IL-1 beta, while only marginally affecting cAMP-induced NOS mRNA levels. Our data suggest that NF kappa B activation is an essential component of the IL-1 beta signalling pathway responsible for NOS gene activation and that cAMP triggers a separate signalling cascade not involving NF kappa B. These observations may provide a basis for the synergistic stimulation of NOS expression by cytokines and cAMP in mesangial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / biosynthesis*
  • Animals
  • Blotting, Northern
  • Bucladesine / pharmacology*
  • Cells, Cultured
  • Cyclic AMP / metabolism*
  • Drug Synergism
  • Enzyme Induction
  • Gene Expression / drug effects*
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / enzymology*
  • Humans
  • Interleukin-1 / pharmacology*
  • Kinetics
  • Nitric Oxide Synthase
  • Nitrites / metabolism
  • Pyrrolidines / pharmacology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / isolation & purification
  • Rats
  • Recombinant Proteins / pharmacology
  • Thiocarbamates / pharmacology*

Substances

  • Interleukin-1
  • Nitrites
  • Pyrrolidines
  • RNA, Messenger
  • Recombinant Proteins
  • Thiocarbamates
  • pyrrolidine dithiocarbamic acid
  • Bucladesine
  • Cyclic AMP
  • Nitric Oxide Synthase
  • Amino Acid Oxidoreductases