Interleukin-1 can inhibit interferon-beta synthesis and its antiviral action: comparison with tumor necrosis factor.
Earlier studies showed that both tumor necrosis factor (TNF) and interleukin-1 (IL1) can inhibit virus replication in cultured cells. However, in human FS-4 fibroblasts, in which recombinant human TNF protected cells from encephalomyocarditis (EMC) virus infection, recombinant human IL1 alpha and IL1 beta failed to induce antiviral protection. Moreover, both forms of IL1 inhibited the development of the TNF-induced antiviral state. To elucidate the mechanism of this inhibition, we examined the effect of IL1 on the synthesis of interferon-beta (IFN-beta), stimulated with polyinosinate.polycytidylate [poly(I).poly(C)]. When added 2 h or more before poly(I).poly(C), both forms of IL1 had a strong inhibitory effect on IFN-beta synthesis, as determined by antiviral assay of the IFN-beta protein or by quantitation of IFN-beta mRNA levels in Northern blot analysis. However, when IL1 was added simultaneously with poly(I).poly(C), or 2 h after poly(I).poly(C), IFN-beta synthesis was increased. The inhibitory action of IL1 on poly(I).poly(C)-induced IFN-beta synthesis was abolished in the presence of cycloheximide, suggesting that it is mediated indirectly by an IL1-induced product in the FS-4 cells. In addition to its ability to inhibit IFN-beta synthesis, IL1 also caused a partial reversal of the antiviral action of IFN-beta. In contrast to IL1, TNF did not inhibit IFN-beta synthesis, nor did it interfere with the antiviral action of IFN-beta. Simultaneous addition of TNF and poly(I).poly(C) to FS-4 cells enhanced IFN-beta synthesis. Under proper conditions TNF and IFN-beta showed an additive antiviral effect.
Kohase
M
M
Department of Microbiology, New York University Medical Center, New York 10016.
Zhang
Y H
YH
Lin
J X
JX
Yamazaki
S
S
Sehgal
P B
PB
Vilcek
J
J
D015152:Blotting, Northern; D003513:Cycloheximide / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000494:pharmacology*; D011070:Poly I-C / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007369:Interferon Inducers; D007370:Interferon Type I; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D011070:Poly I-C