Simvastatin Inhibits IFN Regulatory Factor 4 Expression and Th17 Cell Differentiation in CD4+ T Cells Derived from Patients with Multiple Sclerosis

Abstract

Subsequent to the clinical trial of simvastatin in patients with relapsing remitting multiple sclerosis (RR MS), which demonstrated the ability of simvastatin to inhibit new inflammatory CNS lesion formation, the current in vitro study has characterized the mechanisms through which simvastatin inhibits Th17 cell differentiation. The anti-inflammatory effects of statins are mediated by the inhibition of isoprenylation, which ensures proper membrane insertion and function of proteins. Small GTPases, involved in multiple signal transduction pathways, are the key targets for isoprenylation. We report that simvastatin, one of the most hydrophobic statins with good CNS penetration, inhibited Th17 cell differentiation and IL-17A, IL-17F, IL-21, and IL-22 secretion in in vitro-differentiated naive CD4+ T cells from RR MS patients. Simvastatin exerted a less prominent effect on the cells from healthy controls, as it inhibited only IL-17F secretion. The inhibition of Th17 cell differentiation was mediated via inhibition of IFN regulatory factor 4 (IRF4) expression, which was identified as a key transcription factor for human Th17 cell differentiation using both IRF4 gene knockdown and overexpression experiments. In studies addressing which isoprenylation pathway—geranylgeranylation or farnesylation—is inhibited by simvastatin, we demonstrated that the geranylgeranyl transferase inhibitor replicated the effect of simvastatin. Selective inhibition of geranylgeranylated RhoA-associated kinase replicated the effect of simvastatin on the inhibition of IRF4 expression and IL-17A, IL-17F, IL-21, and IL-22 secretion, presenting a promising new therapeutic approach for this disabling disease.

Cerebrospinal Fluid IL-21 Levels in Neuromyelitis Optica and Multiple Sclerosis

“…Administration of IFN-β to eAe mice ameliorated the disease severity along with decreases in serum levels of Il-21 26 . Other novel therapies, such as simvastatin 27 , curcumin 28 , DNA vaccine 29 , also ameliorated eAe by down-regulating expression of Il-21. Taken together, the results from both in vitro and in vivo experiments suggested evaluating effects of Il-21 in human CNS autoimmune demyelinating disease.…”

Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

“…Recent studies have increasingly highlighted the immunomodulatory role of statins (132–134); and shown in some diseases (other than NAFLD), its potential to interfere in the IL-17 axis, both by inhibiting the differentiation of Th17 cells, decreasing the production of IL-17 (62, 133, 135, 136), and inducing upregulation and recruitment of Treg (133, 137–139), shifting thus T cells response to Treg dominance (134, 140), which has an anti-inflammatory role and is a coordinator of immunologic tolerance (98, 99). This effect was also evident in atherosclerosis where the administration of statins was associated with the accumulation of T regulatory cells in atherosclerotic plaque (141, 142).…”

Adjuvant effects of classical music on simvastatin induced reduction of anxiety but not object recognition memory in rats.

“…Compared with other statins, simvastatin is more lipophilic and more easily permeates the blood-brain barrier, which could offer a further neuroprotective effects (Hayashi et al, 2005;Sierra, Ramos, Molina, Esteo, Vázquez, & Burgos, 2011;Urban et al, 2009). Additionally, evidence indicates that simvastatin reduces the risk of ischemic heart disease and cerebrovascular stroke, with potential applications in multiple sclerosis, traumatic brain injury, Alzheimer's disease, and anxiety and potential effects on cognition (Baytan et al, 2008, Carrocini et al, 2012Sett, Robinson, & Mistri, 2011;Swindle, Potash, Kulakodlu, Kuznik, & Buikema, 2011;Tramontina et al, 2011;Wang et al, 2009;Zhang, Tao, Troiani, & Markovic-Plese, 2011). Despite growing evidence of the role of simvastatin in central nervous system diseases, relatively little knowledge is available about its direct neuropsychological effects on central receptors and association with anxiolytic-like behavioral effects and cognitive decline associated with neurodegenerative diseases (Carrocini et al, 2012;Jukema, Cannon, de Craen, Westendorp, & Trompet, 2012).…”