Abstract:
: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.
journal_name
Mol Immunoljournal_title
Molecular immunologyauthors
Kuijk LM,Mandey SH,Schellens I,Waterham HR,Rijkers GT,Coffer PJ,Frenkel Jdoi
10.1016/j.molimm.2007.12.008subject
Has Abstractpub_date
2008-04-01 00:00:00pages
2158-65issue
8eissn
0161-5890issn
1872-9142pii
S0161-5890(07)00891-7journal_volume
45pub_type
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