JAK inhibitors AG-490 and WHI-P154 decrease IFN-gamma-induced iNOS expression and NO production in macrophages

Mediators Inflamm. 2006;2006(2):16161. doi: 10.1155/MI/2006/16161.

Abstract

In inflammation, inducible nitric oxide synthase (iNOS) produces nitric oxide (NO), which modulates inflammatory processes. We investigated the effects of Janus kinase (JAK) inhibitors, AG-490 and WHI-P154, on iNOS expression and NO production in J774 murine macrophages stimulated with interferon-gamma (IFN-gamma). JAK inhibitors AG-490 and WHI-P154 decreased IFN-gamma-induced nuclear levels of signal transducer and activator of transcription 1alpha (STAT1alpha). JAK inhibitors AG-490 and WHI-P154 decreased also iNOS protein and mRNA expression and NO production in a concentration-dependent manner. Neither of the JAK inhibitors affected the decay of iNOS mRNA when determined by actinomycin D assay. Our results suggest that the inhibition of JAK-STAT1-pathway by AG-490 or WHI-P154 leads to the attenuation of iNOS expression and NO production in IFN-gamma-stimulated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Nucleus / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Interferon-Stimulated Gene Factor 3 / metabolism
  • Interferon-gamma / metabolism*
  • Janus Kinase 1 / antagonists & inhibitors*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / metabolism*
  • Nitrites / metabolism
  • Polymerase Chain Reaction / methods
  • Quinazolines / pharmacology*
  • Tyrphostins / pharmacology*

Substances

  • Enzyme Inhibitors
  • Interferon-Stimulated Gene Factor 3
  • Nitrites
  • Quinazolines
  • Tyrphostins
  • WHI P154
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • gamma interferon activation factor
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
  • Janus Kinase 1