Simvastatin regulates non-neuronal cholinergic activity in T lymphocytes via CD11a-mediated pathways.
Lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. We previously showed that antithymocyte globulin stimulates an independent, non-neuronal cholinergic system in T cells via LFA-1-mediated pathways, as evidenced by increases in acetylcholine (ACh) synthesis and choline acetyltransferase (ChAT) mRNA expression. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. In the present study, we investigated whether simvastatin modulates lymphocytic cholinergic activity in T cells. We found that anti-CD11a monoclonal antibody (mAb) increased ChAT activity, ACh synthesis and release, and expression of ChAT and M5 muscarinic ACh receptor mRNA in MOLT-3 cells, a human leukemic T cell line. Simvastatin abolished these anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. These results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways, and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity.
Fujii
Takeshi
T
Department of Pharmacology, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Tokyo, Japan.
Masuyama
Kazuto
K
Kawashima
Koichiro
K
D000109:Acetylcholine / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D040881:CD11a Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D040881:CD11a Antigen; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D019821:Simvastatin; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine; D008798:Mevalonic Acid