AUTO-ANTIGEN EXPRESSION OF PROTEINASE 3 ON THE MEMBRANE OF NEUTROPHILS IS DEPENDENT ON PHOSPHATIDYLINOSITOL 3- KINASE AND P38 MAPKINASE ACTIVITY

C.G.M. Kallenberg,A.P. Van Rossum, B. Doornbos-van der Meer, P.C. LimburgRheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, NetherlandsObjectives: Expression of the autoantigen proteinase 3 (PR3) on their membrane is a prerequisite for activation of neutrophils by PR3-ANCA. Little is known about the signaling events that translocate the autoantigen PR3 to the membrane in these processes. Therefore, we analyzed involvement of major regulatory cascades as the MAPkinases and phosphatidylinositol3-kinase (PI3-K) during priming and apoptosis in translocation of proteinase 3 to the membrane in order to explore new therapeutic targets in the management of ANCA-associated vasculitis.Methods: Neutrophils were primed with TNFalpha or brought in accelerated apoptosis by treatment with TNFalpha and cycloheximide (CHX) or UV-B irradiation. Pharmacological inhibitors interfering with p38 MAPK, ERK, JNK and PI3-K were added to study their involvement in mPR3 expression.Results: mPR3 induced expression during TNFalpha priming was dependent on p38 MAPK activation only. mPR3 expression induced during TNFalpha/CHX- accelerated apoptosis was dependent on p38 MAPK and PI3K, but not on ERK or JNK. Also, UV-B-accelerated apoptosis resulted in mPr3 expression which was dependent on p38MAPK, but not on PI3-K, ERK or JNK. Interestingly, culture of neutrophils after priming resulted in gradually reduced expression of mPR3 in time.Conclusion: Pharmacological inhibitors interfering with p38 MAPK block expression of mPR3 as induced during priming and apoptosis. As autoantigen expression plays such a dominant role in the pathophysiology of ANCA-associated vasculitis, pharmacological inhibition of p38 MAPK may be an additional therapeutic strategy in the management of ANCA-associated vasculitis.Citation: Ann Rheum Dis, volume 65, supplement II, year 2006, page 380Session: Vasculitis