Extracellular signal-regulated kinase inhibition by statins inhibits neutrophil activation by ANCA.

Extracellular signal-regulated kinase inhibition by statins inhibits neutrophil activation by ANCA. Background 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may modulate cellular inflammatory functions independent of serum cholesterol. We tested the hypothesis that statins decrease respiratory burst activity of human polymorphonuclear neutrophils (PMN) in response to anti-neutrophil cytoplasmic antibodies (ANCA). Methods Neutrophils were isolated from healthy human volunteers, human immunoglobulins were isolated from patients with proteinase-3 (PR3)- and myeloperoxidase (MPO)-ANCA. Superoxide generation was measured by the ferricytochrome C assay and the nitro blue tetrazolium (NBT) test. ANCA antigen expression was measured by flow cytometry and phosphorylation of mitogen-activated protein kinase (MAPK) was assessed by Western blotting. Results Cerivastatin and simvastatin inhibited respiratory burst activity to ANCA dose-dependently (1 to 25 μmol/L). Tumor necrosis factor-α (TNF-α)-primed neutrophils released 26.7 ± 2.8 nmol O 2 - /0.75 × 10 6 PMN/45 min and 10 μmol/L simvastatin reduced this amount to 18.0 ± 2.1 nmol. The inhibitory effect was confirmed by the NBT test. The respiratory burst decrease could not be reversed by 500 μmol/L mevalonic acid (MVA). In this assay, both statins also inhibited the response to human ANCA. PR3-ANCA resulted in 19.4 ± 2.0 nmol O 2 - nmol. This amount was decreased to 6.0 ± 1.2 nmol by preincubation with 10 μmol/L simvastatin ( P P Conclusion These findings demonstrate that HMG-CoA reductase inhibitors decrease respiratory burst activity of human PMN in response to ANCA. This effect was independent of mevalonate, but involved inhibition of ERK activation during TNF-α priming. Our data suggest that HMG-CoA reductase inhibitors may help limit inflammatory responses.