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IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor
G Fantuzzi1, D A Reed, C A Dinarello
1Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Giamila.Fantuzzi@UCHSC.edu
The Journal of Clinical Investigation
|September 24, 1999
Summary
Interleukin-12 (IL-12) induces interferon-gamma (IFN-gamma) partly via interleukin-18 (IL-18). Caspase-1 (ICE) activity and IL-18 are crucial for this IL-12 response in mice.
Area of Science:
- Immunology
- Cytokine signaling
Background:
- Interleukin-12 (IL-12) and Interleukin-18 (IL-18) are key cytokines that induce Interferon-gamma (IFN-gamma).
- The precise mechanism by which IL-12 induces IFN-gamma, particularly the role of endogenous IL-18, requires further elucidation.
Purpose of the Study:
- To investigate the role of endogenous IL-18 in IL-12-induced IFN-gamma production in a mouse model.
- To determine the involvement of caspase-1 (also known as IL-1beta-converting enzyme, or ICE) in this process.
Main Methods:
- Utilized caspase-1 (ICE) inhibitors and splenocytes from ICE-deficient mice.
- Employed neutralizing anti-IL-18 antibodies for in vitro and in vivo experiments.
- Measured IFN-gamma and IL-18 levels in splenocytes and serum following IL-12 administration.
Main Results:
- IL-12-induced IFN-gamma production was significantly reduced (85%) by ICE inhibition and (80%) in ICE-deficient splenocytes.
- Neutralization of IL-18 also reduced IL-12-induced IFN-gamma by 85%.
- IL-12 administration increased circulating IL-18 levels in wild-type mice but not in ICE-deficient mice, correlating with IFN-gamma induction.
Conclusions:
- Endogenous, caspase-1 (ICE)-processed IL-18 plays a significant role in IL-12-mediated IFN-gamma induction.
- The mechanism does not appear to involve the processing and release of IL-1beta.
- These findings highlight a critical interplay between IL-12, IL-18, and ICE in regulating IFN-gamma production.
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