geranylgeranyl-pyrophosphate and Leukemia--Monocytic--Acute

Trafficking of autoreactive leukocytes across the blood-nerve barrier and into peripheral nerves is an early pathological hallmark of Guillain-Barré syndrome (GBS). Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, promotes transendothelial migration by upregulating endothelial expression of inflammatory mediators, including CCL2, a chemokine implicated in GBS. We sought to determine the mechanism by which TNF-α induces expression and secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells (PNMECs). Expression of CCL2 mRNA and protein in quiescent PNMEC cultures was minimal. In contrast, cultures treated with TNF-α exhibited increased CCL2 mRNA and protein content, as well as protein secretion. Simvastatin significantly attenuated TNF-α-induced CCL2 secretion without affecting CCL2 mRNA or protein expression. Co-incubation with geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, prevented the effect of simvastatin. By comparison, inhibiting protein isoprenylation with GGTI-298, but not FTI-277, mimicked the effect of simvastatin and significantly attenuated transendothelial migration in vitro. Inhibition of the monomeric GTPase Cdc42, but not Rac1 or RhoA-C, attenuated TNF-α-mediated CCL2 secretion. TNF-α-mediated trafficking of autoreactive leukocytes into peripheral nerves during GBS may proceed by a mechanism that involves Cdc42-facilitated secretion of CCL2.

Topics: Analysis of Variance; Animals; cdc42 GTP-Binding Protein; Cells, Cultured; Chemokine CCL2; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukemia, Monocytic, Acute; Peripheral Nerves; Polyisoprenyl Phosphates; Prenylation; Rats; RNA, Messenger; Transendothelial and Transepithelial Migration; Tumor Necrosis Factor-alpha

Macrophages secrete matrix metalloproteinase 9 (MMP-9), an enzyme that weakens the fibrous cap of atherosclerotic plaques, predisposing them to plaque rupture and subsequent ischemic events. Recent work indicates that statins strongly reduce the possibility of heart attack. Furthermore, these compounds appear to exert beneficial effects not only by lowering plasma low-density-lipoprotein cholesterol but also by directly affecting the artery wall. To evaluate whether statins influence the proinflammatory responses of monocytic cells, we studied their effects on the chemotactic migration and MMP-9 secretion of human monocytic cell line THP-1. Simvastatin dose dependently inhibited THP-1 cell migration mediated by monocyte chemoattractant protein 1, with a 50% inhibitory concentration of about 50 nM. It also inhibited bacterial lipopolysaccharide-stimulated secretion of MMP-9. The effects of simvastatin were completely reversed by mevalonate and its derivatives, farnesylpyrophosphate and geranylgeranyl pyrophosphate, but not by ubiquinone. Additional studies revealed similar but more profound inhibitory effects with L-839,867, a specific inhibitor of geranylgeranyl transferase. However, alpha-hydroxyfarnesyl phosphonic acid, an inhibitor of farnesyl transferase, had no effect. C3 exoenzyme, a specific inhibitor of the prenylated small signaling Rho proteins, mimicked the inhibitory effects of simvastatin and L-839,867. These data supported the role of geranylgeranylation in the migration and MMP-9 secretion of monocytes.

Topics: ADP Ribose Transferases; Alkyl and Aryl Transferases; Anti-Inflammatory Agents, Non-Steroidal; Botulinum Toxins; Cell Movement; Chemokine CCL2; Chemotaxis; Depression, Chemical; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukemia, Monocytic, Acute; Lipopolysaccharides; Matrix Metalloproteinase 9; Mevalonic Acid; Monocytes; Neoplasm Proteins; Organic Chemicals; Polyisoprenyl Phosphates; Protein Prenylation; Protein Processing, Post-Translational; Sesquiterpenes; Simvastatin; Tumor Cells, Cultured