Temperature and drug treatments in mevalonate kinase deficiency: an ex vivo study.
Mevalonate Kinase Deficiency (MKD) is a rare autosomal recessive inborn disorder of cholesterol biosynthesis caused by mutations in the mevalonate kinase (MK) gene, leading to MK enzyme decreased activity. The consequent shortage of mevalonate-derived isoprenoid compounds results in an inflammatory phenotype, caused by the activation of the NALP3 inflammasome that determines an increased caspase-1 activation and IL-1 β release. In MKD, febrile temperature can further decrease the residual MK activity, leading to mevalonate pathway modulation and to possible disease worsening. We previously demonstrated that the administration of exogenous isoprenoids such as geraniol or the modulation of the enzymatic pathway with drugs, such as Tipifarnib, partially rescues the inflammatory phenotype associated with the defective mevalonic pathway. However, it has not been investigated yet how temperature can affect the success of these treatments. Thus, we investigated the effect of temperature on primary human monocytes from MKD patients. Furthermore the ability of geraniol and Tipifarnib to reduce the abnormal inflammatory response, already described at physiological temperature in MKD, was studied in a febrile condition. We evidenced the role of temperature in the modulation of the inflammatory events and suggested strongly considering this variable in future researches aimed at finding a treatment for MKD.
Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy.
Paola Maura
PM
Tricarico
Giulio
G
Kleiner
Elisa
E
Piscianz
Valentina
V
Zanin
Lorenzo
L
Monasta
Sergio
S
Crovella
Annalisa
A
Marcuzzi
D000080462:Acyclic Monoterpenes; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053898:Biosynthetic Pathways / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D054078:Mevalonate Kinase Deficiency / Q000097:blood / Q000188:drug therapy*; D008798:Mevalonic Acid / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D013696:Temperature; D013729:Terpenes / Q000494:pharmacology / Q000627:therapeutic use*
D000080462:Acyclic Monoterpenes; D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D015363:Quinolones; D013729:Terpenes; C007836:geraniol; C402769:tipifarnib; D008798:Mevalonic Acid