PMID- 12472772
OWN - NLM
STAT- MEDLINE
DCOM- 20040302
LR  - 20141120
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 63
IP  - 1
DP  - 2003 Jan
TI  - Extracellular signal-regulated kinase inhibition by statins inhibits neutrophil 
      activation by ANCA.
PG  - 96-106
AB  - 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 micromol/L). Tumor necrosis factor-alpha 
      (TNF-alpha)-primed neutrophils released 26.7 +/- 2.8 nmol O2-/0.75 x 106 PMN/45 
      min and 10 micromol/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 micromol/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 O2- nmol. This amount was decreased to 6.0 +/- 1.2 nmol by preincubation 
      with 10 micromol/L simvastatin (P < 0.01). For MPO-ANCA, the values were 22.6 +/- 
      2.8 nmol for controls versus 16.7 +/- 3.1 nmol with statin (P < 0.01). By FACS, 
      simvastatin decreased TNF-alpha-mediated ANCA antigen translocation (from 219 +/- 
      33 to 180 +/- 35 MFI for PR3 and 24.0 +/- 2.4 to 18.3 +/- 1.1 for MPO). Finally, 
      since p38 MAPK and ERK control TNF-alpha priming, we studied the effects of both 
      statins on MAPK. Western blotting showed that statins inhibited TNF-alpha-induced 
      ERK phosphorylation in a dose dependent fashion, but had no effect on p38. 
      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-alpha priming. Our data suggest that HMG-CoA reductase inhibitors may help 
      limit inflammatory responses.
FAU - Choi, Mira
AU  - Choi M
AD  - HELIOS Klinkum-Berlin Franz Volhard Clinic and Max Delbruck Center for Molecular 
      Medicine, Medical Faculty of the Charite, Humboldt University of Berlin, Berlin, 
      Germany.
FAU - Rolle, Susanne
AU  - Rolle S
FAU - Rane, Madhavi
AU  - Rane M
FAU - Haller, Hermann
AU  - Haller H
FAU - Luft, Friedrich C
AU  - Luft FC
FAU - Kettritz, Ralph
AU  - Kettritz R
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Antibodies, Antineutrophil Cytoplasmic)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Pyridines)
RN  - 11062-77-4 (Superoxides)
RN  - AGG2FN16EV (Simvastatin)
RN  - AM91H2KS67 (cerivastatin)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - S5UOB36OCZ (Mevalonic Acid)
SB  - IM
MH  - Antibodies, Antineutrophil Cytoplasmic/*pharmacology
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - In Vitro Techniques
MH  - Mevalonic Acid/pharmacology
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors/metabolism
MH  - Neutrophil Activation/*drug effects/*immunology
MH  - Neutrophils/drug effects/enzymology/immunology
MH  - Phosphorylation/drug effects
MH  - Pyridines/*pharmacology
MH  - Respiratory Burst/drug effects/immunology
MH  - Simvastatin/pharmacology
MH  - Superoxides/metabolism
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 2002/12/11 04:00
MHDA- 2004/03/03 05:00
CRDT- 2002/12/11 04:00
PHST- 2002/12/11 04:00 [pubmed]
PHST- 2004/03/03 05:00 [medline]
PHST- 2002/12/11 04:00 [entrez]
AID - S0085-2538(15)48848-9 [pii]
AID - 10.1046/j.1523-1755.2003.00718.x [doi]
PST - ppublish
SO  - Kidney Int. 2003 Jan;63(1):96-106. doi: 10.1046/j.1523-1755.2003.00718.x.