title: Statins directly suppress cytokine production in murine intraepithelial lymphocytes.
abstract: Statins, inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are known not only as cholesterol-lowering agents but also as anti-inflammatory mediators. However, their regulatory effect on intestinal mucosal immunity remains unclear. The present study examined the possible direct effects of statin on intestinal intraepithelial lymphocytes (IELs), the front line cells of the intestinal mucosal immune system. Murine IELs were isolated from the small intestines of C57BL/6 mice. IELs activated with anti-CD3/CD28 monoclonal antibodies produced interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-4 in significant numbers; however, they did not produce IL-5. Both simvastatin and lovastatin suppressed IEL production of IFN-γ, TNF-α, IL-2, and IL-4 in a dose-dependent manner, whereas 48-h treatment with high concentrations (5 × 10(-5)M) of simvastatin and lovastatin did not affect the number of IELs. The suppressive effect of the simvastatin was significantly restored by the addition of mevalonate, farnesyl pyrophosphate ammonium salt, and geranylgeranyl pyrophosphate ammonium salt, which are downstream metabolites of HMG-CoA. These findings suggest that statins have direct suppressive effects on the production of T helper 1-cytokines and IL-4 in IELs; these effects are associated with inhibition of the mevalonate pathway to some extent.
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Jiong
authors.initials: J
authors.lastname: Zhang
authors.forename: Satoshi
authors.initials: S
authors.lastname: Osawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takayanagi
authors.forename: Mutsuhiro
authors.initials: M
authors.lastname: Ikuma
authors.forename: Takanori
authors.initials: T
authors.lastname: Yamada
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Takahisa
authors.initials: T
authors.lastname: Furuta
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyajima
authors.forename: Ken
authors.initials: K
authors.lastname: Sugimoto
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D013997:Time Factors
chemical_list: D000214:Acyl Coenzyme A; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; C004808:farnesyl pyrophosphate; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid