@Article{ecn.2009.0163,
AUTHOR = {Sylvain Normand, Benoit Massonnet, Adriana Delwail, Laure Favot, Laurence Cuisset, Gilles Grateau, Franck Morel, Christine Silvain, Jean-Claude Lecron},
TITLE = {Specific increase in caspase-1 activity and secretion of IL-1 family cytokines: a putative link between mevalonate kinase deficiency and inflammation},
JOURNAL = {European Cytokine Network},
VOLUME = {20},
YEAR = {2009},
NUMBER = {3},
PAGES = {101--107},
URL = {http://www.techscience.com/ECN/v20n3/65894},
ISSN = {1952-4005},
ABSTRACT = {The mevalonate kinase deficiency (MKD), including hyperimmunoglobulinemia D periodic fever
syndrome (HIDS) and the more severe mevalonic aciduria are rare, autosomal recessive, autoinflammatory dis-eases
belonging to the hereditary periodic fever (HPF) family. Other members include: familial mediterranean
fever (FMF), the cryopyrin-associated periodic syndromes (CAPS) and TNFR-associated periodic syndromes
(TRAPS). MKD is caused by mutations in the gene encoding mevalonate kinase (MK), an enzyme of the choles-terol
pathway, leading to its inactivation. The molecular mechanisms linking MKD and abnormalities of iso-prenoid
biosynthesis to cytokine production and inflammation have yet to be fully elucidated. Statins, which
are extensively prescribed for lowering cholesterol, are potent inhibitors of 3-hydroxy-3-methylglutaryl-CoA
reductase, the enzyme directly upstream of MK. In this review, we discuss recent reports demonstrating that in
vitro inhibition of the mevalonate pathway by statins specifically increases the production, by activated mono-cytes,
of cytokines of the IL-1 family, by enhancing caspase-1 activity, the enzyme responsible for IL-1β and
IL-18 maturation. The molecular mechanisms involve geranylgeranylation and the enhancement of the activity
of G proteins such as Rac-1. Interestingly, activated fibroblasts from MKD patients secrete more IL-1β than
fibroblasts from healthy donors. Taken together, these data highlight the specific enhancement of the IL-1
family of cytokines, the maturation of which is caspase-1-dependent in MKD. Finally, the spectacular decrease
in febrile attacks in patients with severe HIDS under IL-1 receptor antagonist (anakinra) treatment, reinforces
this hypothesis. Deregulated caspase-1 activation could be responsible for the inflammatory component of
MKD, thereby mechanistically linking MKD to FMF and CAPS through cytokines of the IL-1 family.},
DOI = {10.1684/ecn.2009.0163}
}