Premium
Interleukin‐4‐Mediated Inhibition of Nitric Oxide Production in Interferon‐γ‐Treated and Virus‐Infected Macrophages
Author(s) -
Søren R. Paludan,
Svend Ellermann-Eriksen,
Jette Lovmand,
Søren C. Mogensen
Publication year - 1999
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1046/j.1365-3083.1999.00495.x
Subject(s) - stat1 , janus kinase , irf1 , stat protein , nitric oxide synthase , interferon , jak stat signaling pathway , interferon regulatory factors , nitric oxide , biology , microbiology and biotechnology , stat , stat3 , transcription factor , herpes simplex virus , signal transduction , chemistry , virus , immunology , tyrosine kinase , gene , endocrinology , biochemistry
Upon interferon‐γ (IFN‐γ) stimulation, murine macrophages (MΦ) produce nitric oxide (NO) through expression of inducible nitric oxide synthase (iNOS). Interleukin (IL)‐4 treatment, even delayed 12 h relative to IFN‐γ, antagonized this induction, whereas infection with herpes simplex virus type 2 (HSV‐2) or treatment with tumour necrosis factor‐α exerted a synergistic effect, which partly compensated for the antagonistic effect of IL‐4. Neither IL‐4 nor HSV‐2 affected the IFN‐γ‐activated Jak–STAT (Janus kinase–signal transducer and activator of transcription) pathway or altered the levels of IFN‐γ‐induced interferon regulatory factor (IRF)‐1 expression, which is STAT1‐dependent and known to play a central role in IFN‐γ‐mediated gene induction. The effect of IL‐4 was completely dependent on de novo protein synthesis, indicating that a direct activation of latent inhibitors is not sufficient to explain the inhibitory effect of IL‐4. Furthermore, IL‐4 substantially augmented the IFN‐γ‐induced expression of IRF‐2, which is known to compete with IRF‐1 for the DNA recognition site, ISRE (interferon‐stimulated response element). Our findings could indicate that IL‐4 suppresses IFN‐γ‐stimulated iNOS transcription by elevating the level of IRF‐2 which, through competition, prevents IRF‐1 from binding to ISRE in the iNOS promoter. The virus‐induced effects on iNOS and NO levels in IFN‐γ‐stimulated MΦ do not seem to involve the Jak/STAT pathway or a differential expression of IRF‐1 and IRF‐2.