Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells.
Interleukin (IL)-18, formerly called interferon gamma (IFN-gamma)-inducing factor, is biologically and structurally related to IL-1beta. A comparison of gene expression, synthesis, and processing of IL-18 with that of IL-1beta was made in human peripheral blood mononuclear cells (PBMCs) and in human whole blood. Similar to IL-1beta, the precursor for IL-18 requires processing by caspase 1. In PBMCs, mature but not precursor IL-18 induces IFN-gamma; in whole human blood stimulated with endotoxin, inhibition of caspase 1 reduces IFN-gamma production by an IL-1beta-independent mechanism. Unlike the precursor for IL-1beta, precursor for IL-18 was expressed constitutively in PBMCs and in fresh whole blood from healthy human donors. Western blotting of endotoxin-stimulated PBMCs revealed processed IL-1beta in the supernatants via an caspase 1-dependent pathway. However, in the same supernatants, only unprocessed precursor IL-18 was found. Unexpectedly, precursor IL-18 was found in freshly obtained PBMCs and constitutive IL-18 gene expression was present in whole blood of healthy donors, whereas constitutive IL-1beta gene expression is absent. Similar to human PBMCs, mouse spleen cells also constitutively contained the preformed precursor for IL-18 and expressed steady-state IL-18 mRNA, but there was no IL-1beta protein and no spontaneous gene expression for IL-1beta in these same preparations. We conclude that although IL-18 and IL-1beta are likely members of the same family, constitutive gene expression, synthesis, and processing are different for the two cytokines.
Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
A J
AJ
Puren
G
G
Fantuzzi
C A
CA
Dinarello
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000097:blood / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D013154:Spleen / Q000276:immunology; D014158:Transcription, Genetic
D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007371:Interferon-gamma