TY - JOUR
T1 - The inhibition of mevalonate pathway induces upregulation of NALP3 expression
T2 - New insight in the pathogenesis of mevalonate kinase deficiency
AU - Pontillo, Alessandra
AU - Paoluzzi, Elisa
AU - Crovella, Sergio
PY - 2010/7
Y1 - 2010/7
N2 - Mevalonate kinase deficiency (MKD) is a rare hereditary auto-inflammatory syndrome due to mutations in mevalonate kinase, the second enzyme of mevalonate pathway of cholesterol, and nonsterol-isoprenoids biosynthesis. The shortage of mevalonate-derived intermediates, and in particular of geranylgeranyl pyrophosphate (GGPP), has been linked with the activation of caspase-1 and thereby with the production of IL-1Β, but the true concatenation of these two events has not been clarified yet. We hypothesized that inflammasomes could mediate the activation of caspase-1 due to the shortage of GGPP. We monitored the expression of the principal proteins (NALP1, NALP3 and IPAF) of the three known inflammasomes, first in a cellular model of MKD and then in two MKD patients, after bacterial lipopolysaccharide (LPS) stimulation. In healthy subjects, alendronate alone induced the expression of NALP1 and NALP3, and then together with LPS it induced a dramatic increase in NALP3 expression. In MKD patients, NALP3 expression was higher than in untreated healthy controls. Our results, although preliminary, showed that the inhibition of the mevalonate pathway led to a hyper-expression of NALP3, suggesting a possible involvement of NALP3-inflammasome in the activation of caspase-1 consequent to GGPP decrement. This is the first time that the involvement of the inflammasome complexes was shown in MKD pathogenesis.
AB - Mevalonate kinase deficiency (MKD) is a rare hereditary auto-inflammatory syndrome due to mutations in mevalonate kinase, the second enzyme of mevalonate pathway of cholesterol, and nonsterol-isoprenoids biosynthesis. The shortage of mevalonate-derived intermediates, and in particular of geranylgeranyl pyrophosphate (GGPP), has been linked with the activation of caspase-1 and thereby with the production of IL-1Β, but the true concatenation of these two events has not been clarified yet. We hypothesized that inflammasomes could mediate the activation of caspase-1 due to the shortage of GGPP. We monitored the expression of the principal proteins (NALP1, NALP3 and IPAF) of the three known inflammasomes, first in a cellular model of MKD and then in two MKD patients, after bacterial lipopolysaccharide (LPS) stimulation. In healthy subjects, alendronate alone induced the expression of NALP1 and NALP3, and then together with LPS it induced a dramatic increase in NALP3 expression. In MKD patients, NALP3 expression was higher than in untreated healthy controls. Our results, although preliminary, showed that the inhibition of the mevalonate pathway led to a hyper-expression of NALP3, suggesting a possible involvement of NALP3-inflammasome in the activation of caspase-1 consequent to GGPP decrement. This is the first time that the involvement of the inflammasome complexes was shown in MKD pathogenesis.
KW - Caspase-1
KW - Inflammasome
KW - Mevalonate kinase deficiency
KW - NALP3
UR - http://www.scopus.com/inward/record.url?scp=77953806728&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953806728&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2010.9
DO - 10.1038/ejhg.2010.9
M3 - Article
C2 - 20179743
AN - SCOPUS:77953806728
VL - 18
SP - 844
EP - 847
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 7
ER -