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Interleukin-18 Regulation of Interferon  Production and Cell
Proliferation as Shown in Interleukin-1 -Converting Enzyme
(Caspase-1)-Deficient Mice
Giamila Fantuzzi,
Adrian J. Puren,
Matthew W. Harding,
David J. Livingston, and
Charles A. Dinarello
From the Division of Infectious Diseases, University of Colorado
Health Sciences Center, Denver, CO; and the Vertex Pharmaceuticals,
Inc, Cambridge, MA.
Interleukin-18 (IL-18) is a costimulatory factor for interferon
(IFN) production. Processing of pro-IL-18 by IL-1 -converting enzyme (ICE) leads to the release of bioactive IL-18. Compared with
wild-type (WT) mice, splenocytes from ICE-deficient mice produced low
IFN after lipopolysaccharide (LPS) or zymosan (50% and 80%
reduction). In contrast, IFN 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 IFN was also reduced by an ICE inhibitor.
Exogenous IL-18 augmented zymosan-induced IFN production in WT mice.
In ICE-deficient cells, IFN production was only partially restored
by IL-18. The reduced levels of IFN 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. IFN 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 IFN inhibited, whereas blockade of endogenous
IFN 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 IFN 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.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2118-2125
© 1998 by The American Society of Hematology.
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