Effect of HMG-CoA reductase inhibition on ANCA-mediated neutrophil activation


Auto-antibodies to cytoplasmic constituents of neutrophils (ANCA or anti-neutrophil cytoplasmic antibodies) activate neutrophils and monocytes in vitro. Priming the cells with a subactivating concentration of inflammatory cytokines such as TNF-alpha is necessary to enable ANCA to trigger full-blown neutrophil activation. ANCA bind to their target-antigens on the surface of neutrophils and activate several cellular responses. This project will focuss on the intracellular signaling mechanisms that mediate both TNF-alpha priming and ANCA-induced activation. We will test the hypothesis that HMG-CoA reductase inhibitors block the ANCA-mediated generation of oxygen radicals. These studies will characterize novel non-immunosuppressive treatment protocols to control vascular inflammation in ANCA-associated systemic vasculitis
Head of Project:

Univ. Prof. Dr. Ralph Kettritz
Charité - Universitätsmedizin Berlin
Department of Internal Medicine, Nephrology and Hypertensiology CBB
Tel. 450-540281
Fax 450-540984
kettritz@charite.de
Additional Member of Project:

Dr. Mira Choi
Begin/End of Project:

01/2002 - 12/2010
Funded by:

Spende
Publications:

Falk RJ, Terrell RS, Charles LA, Jennette JC: Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A 1990;87:4115-9 Kettritz R, Jennette JC, Falk RJ: Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils. J Am Soc Nephrol 1997;8: 386-94 Yokota T, Utsunomiya K, Murakawa Y, Kurata H, Tajima N: Mechanism of preventive effect of HMG-CoA reductase inhibitor on diabetic nephropathy. Kidney Int 56 Suppl 71: S178-81, 1999 Dunzendorfer S, Rothbucher D, Schratzberger P, Reinisch N, Kahler CM, Wiedermann CJ: Mevalonate-dependent inhibition of transendothelial migration and chemotaxis of human peripheral blood neutrophils by pravastatin. Circ Res 1997;81:963-9 Rosenson RS, Tangney CC, Casey LC: Inhibition of proinflammatory cytokine production by pravastatin [letter]. Lancet 1999;353:983-4