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Characterization of the Regulation and Functional Consequences of p21^ras Activation in Neutrophils by Antineutrophil Cytoplasm Antibodies

Renal Immunobiology, MRC Centre for Immune Regulation, The Medical School, University of Birmingham, Birmingham, United Kingdom

Address correspondence to: Prof. Caroline O.S. Savage, Renal Immunobiology, MRC Centre for Immune Regulation, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK. Phone: +44-121-414-6841; Fax: +44-121-414-6840; E-mail: c.o.s.savage{at}bham.ac.uk

Antineutrophil cytoplasm antibodies (ANCA) are implicated in the pathogenesis of systemic vasculitis. ANCA are directed against antigens expressed on the surface of cytokine-primed neutrophils. It was shown previously that whole IgG ANCA and its fraction antigen binding [F(ab')₂] fragment can activate the GTPase p21^ras. This study shows a functional involvement of this molecule in the ANCA activation of neutrophils by inhibiting the production of superoxide with farnesylthiosalicylic acid. Using the ras activation assay, farnesylthiosalicylic acid inhibits p21^ras binding to its substrate at comparable concentrations to those seen for superoxide inhibition. It is also shown that activation of p21^ras by ANCA is transient, peaking at 5 to 10 min and returning to baseline by 30 min. The use of ras isoform–specific antibodies in Western blots established, for the first time, that Harvey-ras is not present in human neutrophils, but both Kirsten-ras (K-ras) and Neuronal-ras are. Stimulation with ANCA is able to differentially activate K-ras without effects on neuronal-ras. The activation of p21^ras by ANCA and its F(ab')₂ is prevented by inhibition of both Src kinases and phosphatidylinositol-3-kinase, indicating a cooperative role for both molecules in the G protein pathway activated by ANCA F(ab')₂ upstream of p21^ras. It is concluded that ANCA selectively activates K-ras during induction of a respiratory burst via pathways involving multiple upstream kinases.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673