Statin synergizes with LPS to induce IL-1beta release by THP-1 cells through activation of caspase-1.
Mevalonate kinase deficiency (MKD) is a hereditary syndrome characterized by recurring episodes of fever and inflammation. Peripheral blood mononuclear cells from MKD patients secrete high levels of interleukin (IL)-1beta when stimulated with lipopolysaccharide (LPS), which is thought to be a primary cause of the inflammation. However, the link between a deficient mevalonate kinase and excessive IL-1beta release remains unclear. To investigate this we made use of a model in which monocytic cells (THP-1) were treated with simvastatin. Statins are compounds that inhibit 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase and thereby artificially impair the isoprenoid biosynthesis pathway, mimicking mevalonate kinase deficiency. Our study revealed that LPS-stimulated THP-1 cells treated with simvastatin had an increased caspase-1 mediated processing of proIL-1beta. This increased processing was caused by enhanced autoprocessing of caspase-1, rather than enhanced transcription or translation of caspase-1 or proIL-1beta. Simvastatin-induced activation of caspase-1 was caused by an impairment of non-sterol isoprenoid biosynthesis, as the isoprenyl intermediate GGPP could block activation of caspase-1 and mIL-1beta release. In addition, inhibition of both farnesyl pyrophosphate synthase and geranylgeranyltransferase I also induce mIL-1beta release. Taken together, these results demonstrate that simvastatin augments LPS-induced IL-1beta release post-translationally, by inducing caspase-1 activity. These findings suggest that MKD patients may have overactive caspase-1, causing enhanced IL-1beta processing and subsequent inflammation in response to bacterial components.
Kuijk
Loes M
LM
Department of General Pediatrics, Division of Pediatrics, University Medical Center, Utrecht, The Netherlands.
Mandey
Saskia H
SH
Schellens
Ingrid
I
Waterham
Hans R
HR
Rijkers
Ger T
GT
Coffer
Paul J
PJ
Frenkel
Joost
J
D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011498:Protein Precursors; D012333:RNA, Messenger; D019821:Simvastatin; D020170:Caspase 1