Statins, widely used cholesterol-lowering agents, have also been demonstrated to have anti-inflammatory effects. Here we characterize the capacity of simvastatin to target DCs and modulate T-cell priming and Th17-cell differentiation, in a cohort of patients with relapsing remitting multiple sclerosis(RRMS). We report that simvastatin inhibits IL-1β, IL-23, TGF-β, IL-21, IL-12p70 and induces IL-27 secretion from DCs in RRMS patients, providing an inhibitory cytokine milieu for Th17 and Th1-cell differentiation. The effect on DCs is mediated via induction of SOCS1, SOCS3 and SOCS7 gene expression, which are associated with the inhibition of STAT1, STAT3 and ERK1/2 phosphorylation. A geranylgeranyl transferase inhibitor (GGTI) replicated simvastatin's effects on DC cytokine secretion, implicating that simvastatin-induced depletion of isoprenoids mediates this effect. Simvastatin inhibited antigen presentation by DCs via suppression of the MHC class I expression, costimulatory molecules CD80 and CD40, and by inducing a dramatic loss of dendritic processes. The changes in DC morphology were also mediated via inhibition of geranylgeranylation. The therapeutic use of geranylgeranylation inhibitors may provide selective inhibition of key pathogenic cytokines that drive the autoimmune response in MS; their use represents a promising therapeutic approach that requires further clinical testing.
Last week we had evidence of Simvastatin doing something in progressive MSers and here we have evidence that it does something on the immune system. Statins inhibit the production of cholesterol but can do other things.
This work indicates that the effect is mediated by isoprenoids in the pathway involved in chloresterol inhibition. Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic
molecules to a protein
. Geranylgeranylation is a form of prenylation
, which is a post-translational modification
of proteins that involves the attachment of one or two 20-carbon lipophilic geranylgeranyl isoprene
units from geranylgeranyl diphosphate
to one or two cysteine
residue(s) at the C-terminus
of specific proteins. Prenylation (including geranylgeranylation) is thought to function, at least in part, as a membrane anchor for proteins. In the pathway one route is to may cholesterol another thing the isoprenoids do is activate Rho. This is involved the arrangement of the cell skeleton and so can effect cell processes.
Team G and friends showed
that geranylgeranylation inhibitors (and statins) may inhibit EAE years ago. However the evidence that statins inhibit the immune response to any major effect is slim in MS, so why will these fair better? I guess we shall see if they are developed.
Labels: dendritic cells, simvastatin, statins