The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C.
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-1β. However, in this study, we report that caspase-1 is not required in vivo for much of the IL-1β-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-1β, 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-1β 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-1β, indicating that cathepsin C and caspase-1 function upstream of IL-1β, and, in their absence, all components of the pathway downstream of mature IL-1β are intact.
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
Hajime
H
Kono
Gregory M
GM
Orlowski
Zubin
Z
Patel
Kenneth L
KL
Rock
D000818:Animals; D001202:Ascitic Fluid / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000172:deficiency / Q000502:physiology*; D020789:Cathepsin C / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D058847:Inflammasomes / Q000276:immunology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000502:physiology*; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology
D058847:Inflammasomes; D007375:Interleukin-1; D020789:Cathepsin C; D020170:Caspase 1