Interaction of Transforming Growth Factor ß (TGFß) with Proteinase 3

Summary

TGFß is a multifunctional cytokine modulating onset and course of autoimmune diseases as shown in experimental models. Aim of this study was to investigate possible interactions of TGFß with lysosomal enzymes identified as ANCA autoantigens (e.g. proteinase 3, PR3). This included TGFß effects on the translocation the lysosomal enzymes to the cell surface ofpolymorphonuclear cells (PMN), and the presumabe activation of non bioactive, latent TGFß by these enzymes. Flow cytometry analysis showed TGFß1 to be a potent translocation factor for PR3 comparable with other neutrophil activating factors such as irtterleukin 8 (1 L8). The PR3 membrane expression on primed PMN increased by up to 51% after incubation with TGFß1. PR3 itself was revealed as a potent activator of latent TGFß, thus mediating bioeffects of this cytokine. Patients with various types of systemic vasculitis (SV) showed marked TGFß overexpression correlating with disease. Mean TGFßI plasma levels in the ANCA associated vasculitis (AAV) patients ranged from 8.9 (Wegeners granulomatosis, WG) to 13.3 ng/ml (Churg-Strauss syndrome, CSS) (control: 4.2 ng/ml, p<0.01) while TGFß2 levels were not elevated. Our findings, together with other features of TGFß’s such as induction of angiogenesis and its strong chemotactic capacity, indicate that TGFß might serve as a proinflammatory factor in SV, especially in AAV.