Medline ® Abstract for Reference 46
Statin synergizes with LPS to induce IL-1beta release by THP-1 cells through activation of caspase-1.
Kuijk LM, Mandey SH, Schellens I, Waterham HR, Rijkers GT, Coffer PJ, Frenkel J
Mol Immunol. 2008;45(8):2158. Epub 2008 Feb 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-1betarelease. 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.
Department of General Pediatrics, Division of Pediatrics, University Medical Center, Utrecht, The Netherlands.