期刊
JOURNAL OF IMMUNOLOGY
卷 189, 期 7, 页码 3734-3740出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1200136
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资金
- National Institutes of Health
- Diabetes Endocrinology Research Center [DK32520]
- Grant for Research on Intractable Diseases from the Ministry of Health, Labour, and Welfare
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Public Trust Cardiovascular Research Fund
- Senshin Medical Research Foundation
- Kowa Life Science Foundation
- Naito Foundation
- Takeda Science Foundation
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Medical Scientist Training Program Training Grant from the National Institutes of Health [T32 AI095213-01]
The sterile inflammatory response to cell death and irritant crystals is medically important because it causes disease. Although these stimuli are structurally distinct, they cause inflammation through a common pathway that requires the cytokine IL-1. In vitro, the inflammasome, and in particular its generation of active caspase-1, is absolutely required to produce bioactive IL-1 beta. However, in this study, we report that caspase-1 is not required in vivo for much of the IL-1 beta-dependent sterile inflammatory response. Furthermore, we find that cathepsin C, which controls the activity of a number of leukocyte serine proteases capable of processing IL-1 beta, plays a major role in this caspase-1-independent pathway. Mice that are deficient in cathepsin C have reduced inflammatory responses to dying cells and silica crystals. In the absence of cathepsin C, caspase-1 becomes rate limiting such that mice doubly deficient in both of these proteases make little IL-1 beta in vivo and have markedly attenuated inflammatory responses to the sterile stimuli. In contrast, these mutant mice generate normal inflammation in response to exogenous IL-1 beta, indicating that cathepsin C and caspase-1 function upstream of IL-1b, and, in their absence, all components of the pathway downstream of mature IL-1 beta are intact. The Journal of Immunology, 2012, 189: 3734-3740.
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