Downregulation of Newcastle disease virus (NDV)-dependent IFN-alpha/beta production in macrophages by IFN-induced gene products of the locus If-1.
We have found that in cultured mouse bone-marrow-derived macrophages (BMDM), endogenous IFN-beta specifically regulates Newcastle disease virus (NDV) induced interferon (IFN)-alpha/beta synthesis, possibly by influencing the activity of genes within the regulatory locus If-1. Comparison of anti-IFN-beta-treated BMDM from C57BL/6 mice and the congenic line B.6C-H28c carrying the high (h) or low (l) producer allele of If-1, respectively, revealed a much stronger response of the If-1l allele to exogenous IFN-alpha treatment. Twenty IU rIFN-alpha 4 were sufficient to induce nearly complete suppression of NDV-induced IFN-alpha and IFN-beta production in BMDM from B6.C-H28c mice, but had no effect on the IFN-alpha/beta response induced by Sendai virus, another member of the paramyxovirus group. Simultaneous treatment of BMDM with cycloheximide inhibited the suppressive effect of rIFN-alpha 4, indicating that IFN induced the expression of one or several new proteins encoded by gene(s) within the If-1l locus which are responsible for the NDV-specific downregulation of IFN-alpha/beta production. A time course analysis indicated that the suppressive activity of IFN-induced If-1l gene products took 12 h to develop. It was preceded by an opposite priming effect, leading to enhancement of the early IFN-alpha/beta response to NDV measured 5 h after infection. This priming effect in BMDM was, however, only visible during an 8-h period of IFN-alpha treatment, whereas in the continued presence of IFN for 12 h or longer, priming was superimposed by the inhibitory action of the If-1l gene products.(ABSTRACT TRUNCATED AT 250 WORDS)
Zawatzky
R
R
Institute of Virus Research, German Cancer Research Center, Heidelberg.
Wurmbaeck
H
H
D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005809:Genes, Regulator; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000276:immunology; D009521:Newcastle Disease / Q000235:genetics / Q000276:immunology; D009522:Newcastle disease virus / Q000276:immunology*
D016898:Interferon-alpha; D016899:Interferon-beta