Interaction of transforming growth factor β (TGFβ) with proteinase 3

TGFβ is a multifunctional cytokine modulating onset and course of autoimmune diseases as shown in experimental methods. Aim of this study was to investigate possible interactions of TGFβ with lysosomal enzymes identified as ANCA autoantigens (e.g. proteinase 3, PR3). This included TGFβ effects on the translocation the lysosomal enzymes to the cell surface of polymorphonuclear cells (PMN), and the presumable activation of non bioactive, latent TGFβ by these enzymes. Flow cytometry analysis showed TGFβ1 to be a potent translocation factor for PR3 comparable with other neutrophil activating factors such as interleukin 8 (IL8). The PR3 membrane expression on primed PMN increased by up to 51% after incubation with TGFβ1. PR3 itself was revealed as a potent activator of latent TGFβ, thus mediating bioeffects of this cytokine. Patients with various types of systemic vasculitis (SV) showed marked TGFβ overexpression correlating with disease. Mean TGFβ1 plasma levels in the ANCA associated vasculitis (AAV) patients ranged from 8.9 (Wegeners granulomatosis, WG) to 13.3 ng/ml (Chung-Strauss syndrome, CSS) (control: 4.2 ng/ml, p<0.01) while TGFβ2 levels were not elevated. Our findings, together with other features of TGFβ's such as induction of angiogenesis and its strong chemotactic capacity, indicate that TGFβ might serve as a proinflammatory factor in SV, especially in AAV.