title: IL-1 induces IL-1. IV. IFN-gamma suppresses IL-1 but not lipopolysaccharide-induced transcription of IL-1.
abstract: IL-1 induces its own gene expression in human PBMC, in cultured smooth muscle and in endothelial cells. IL-1-induced IL-1 may be part of a self-amplification or an autocrine growth factor in a variety of responses, and thus the endogenous regulation of IL-1 production likely contributes to the outcome of immunologic or inflammatory responses. In the present study, IFN-gamma consistently increased LPS-induced IL-1, but reduced the total amount of IL-1-induced IL-1 from PBMC. This reduction was observed in populations of adherent cells and cells selected with anti-Leu M3 antibody. On a molar basis, IFN-gamma and IFN-alpha 2 were equally effective in reducing IL-1-induced IL-1 synthesis. In PBMC of 24 human subjects, IFN-gamma also reduced PMA-induced IL-1 synthesis (67% decrease, p less than 0.001). The augmentation of LPS-stimulated IL-1 by IFN-gamma was observed only when added at the same time as LPS, but IFN-gamma could be added 6 h after stimulation with IL-1 and still suppress IL-1 production. LPS-induced mRNA for IL-1 beta was modestly enhanced by IFN-gamma whereas mRNA levels for TNF were markedly increased. In contrast, IFN-gamma suppressed mRNA accumulation for IL-beta after stimulation with IL-1 alpha by 60 to 95%. The addition of IFN-gamma 30 min before stimulation of PBMC with IL-1 suppressed IL-1 beta mRNA for up to 30 h. The half-life of IL-1 beta mRNA of approximately 2 h was not influenced by IFN-gamma. Thus, IFN-gamma reduces IL-1-induced IL-1 synthesis by suppressing IL-1-induced transcription, whereas the same concentrations of IFN-gamma augment LPS-induced IL-1 production by increasing transcription.
authors.affiliation: Department of Medicine, Tufts University School of Medicine, Boston, MA.
authors.forename: R
authors.initials: R
authors.lastname: Schindler
authors.forename: P
authors.initials: P
authors.lastname: Ghezzi
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D002448:Cell Adhesion; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D007370:Interferon Type I; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate