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

Outi Sareila1, Riku Korhonen, Outi Kärpänniemi

  • 1The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, 33014 Tampere, Finland.

Mediators of Inflammation
|August 3, 2006
PubMed

Insights

Janus kinase (JAK) inhibitors AG-490 and WHI-P154 reduce inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in macrophages. This occurs by inhibiting the JAK-STAT1 pathway, crucial in inflammatory responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Inducible nitric oxide synthase (iNOS) plays a key role in inflammatory processes by producing nitric oxide (NO).
  • The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, particularly STAT1alpha, is involved in regulating inflammatory gene expression.

Purpose of the Study:

  • To investigate the impact of JAK inhibitors AG-490 and WHI-P154 on iNOS expression and NO production.
  • To elucidate the role of the JAK-STAT1 pathway in modulating iNOS and NO levels in response to interferon-gamma (IFN-gamma).

Main Methods:

  • J774 murine macrophages were stimulated with IFN-gamma.
  • The effects of JAK inhibitors AG-490 and WHI-P154 on nuclear STAT1alpha levels, iNOS protein and mRNA expression, and NO production were assessed.
  • mRNA decay was evaluated using the actinomycin D assay.

Main Results:

  • AG-490 and WHI-P154 significantly decreased IFN-gamma-induced nuclear STAT1alpha levels.
  • Both JAK inhibitors reduced iNOS protein and mRNA expression in a concentration-dependent manner.
  • NO production was attenuated by AG-490 and WHI-P154, without affecting iNOS mRNA stability.

Conclusions:

  • Inhibition of the JAK-STAT1 pathway by AG-490 or WHI-P154 effectively attenuates iNOS expression and NO production.
  • These findings highlight the JAK-STAT1 pathway as a potential therapeutic target for inflammatory conditions involving iNOS and NO.

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