Interleukin-18 regulation of interferon gamma production and cell proliferation as shown in interleukin-1beta-converting enzyme (caspase-1)-deficient mice.
Interleukin-18 (IL-18) is a costimulatory factor for interferongamma (IFNgamma) production. Processing of pro-IL-18 by IL-1beta-converting enzyme (ICE) leads to the release of bioactive IL-18. Compared with wild-type (WT) mice, splenocytes from ICE-deficient mice produced low IFNgamma after lipopolysaccharide (LPS) or zymosan (50% and 80% reduction). In contrast, IFNgamma production was unimpaired in ICE-deficient mice using Concanavalin A (Con A). Comparable results were obtained when endogenous IL-18 was blocked with a neutralizing antibody. LPS-induced IFNgamma was also reduced by an ICE inhibitor. Exogenous IL-18 augmented zymosan-induced IFNgamma production in WT mice. In ICE-deficient cells, IFNgamma production was only partially restored by IL-18. The reduced levels of IFNgamma in ICE-deficient mice were not due to a lack of IL-12, because zymosan induced IL-12 equally in WT and in ICE-deficient mice. IFNgamma is an important regulator of cell proliferation. In accordance, splenocytes from ICE-deficient mice proliferated more when stimulated with LPS, but not with Con A. Furthermore, in ovalbumin-sensitized ICE-deficient mice, proliferation of lymph node cells in response to the specific antigen was not altered. Exogenous IFNgamma inhibited, whereas blockade of endogenous IFNgamma or IL-18 increased, LPS induced splenocyte proliferation both in WT and in ICE-deficient mice. Our results show that IL-18 is an IL-12-independent regulator of IFNgamma production and of cell proliferation induced by microbial stimuli. However, ICE-dependent processing of IL-18 is not needed for response to mitogens or antigens.
Fantuzzi
G
G
Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Puren
A J
AJ
Harding
M W
MW
Livingston
D J
DJ
Dinarello
C A
CA
D000818:Animals; D020170:Caspase 1; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D020382:Interleukin-18; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D015054:Zymosan / Q000494:pharmacology
D016207:Cytokines; D020382:Interleukin-18; D008070:Lipopolysaccharides; D003208:Concanavalin A; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin; D015054:Zymosan; D003546:Cysteine Endopeptidases; D020170:Caspase 1