Antiviral and immunoregulatory activities of IFN-gamma depend on constitutively expressed IL-1alpha.
IFN-gamma induces its immunoregulatory activities by activating genes mainly through the Jak-STAT signaling pathway. Here we show that what was considered to be intrinsic IFN-gamma activities depend largely on the basal level of NF-kappaB, which is maintained by constitutively expressed IL-1alpha. The IL-1 receptor antagonist and antibodies to IL-1alpha, but not to IL-1beta, inhibited the antiviral activity of IFN-gamma by 90%, whereas no inhibition of type I IFN activity was observed. Similarly, the induction of many genes by IFN-gamma, including HLA-DR, ICAM-1, IL-18BP, and genes mediating its antiviral activity, greatly depended on basal IL-1alpha. Furthermore, IFN-gamma induced serum IL-18 binding protein in wild-type mice but not in IL-1alpha/beta double-deficient mice. Thus, constitutively expressed IL-1alpha is critical for numerous IFN-gamma activities.
Hurgin
Vladimir
V
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
Novick
Daniela
D
Werman
Ariel
A
Dinarello
Charles A
CA
Rubinstein
Menachem
M
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology*; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; D036341:Intercellular Signaling Peptides and Proteins; D050856:Interferon Regulatory Factor-1; D053582:Interleukin-1alpha; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; C118370:interleukin-18 binding protein; D007371:Interferon-gamma