Transforming growth factor-beta (TGF-beta) expression and interaction with proteinase 3 (PR3) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
TGF-beta is a multifunctional cytokine modulating the onset and course of autoimmune diseases as shown in experimental models. The aim of this study was to investigate TGF-beta expression in ANCA-associated vasculitis (AAV), and the possible interactions of this cytokine with lysosomal enzymes identified as ANCA autoantigens (e.g. PR3). This included TGF-beta effects on the translocation of the lysosomal enzymes to the cell surface of polymorphonuclear neutrophils (PMN), and the presumed activation of non-bioactive, latent TGF-beta by these enzymes. Patients with various types of systemic vasculitis (SV) were studied, including three different types of AAV (Wegener's granulomatosis (WG), Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MPA)). Regardless of the type of assay applied, the TGF-beta 1 isoform was found to be over-expressed in SV, including AAV, and to correlate with disease activity as shown for WG. Mean TGF-beta 1 plasma levels in AAV patients ranged from 8.9 ng/ml (WG) to 13.3 ng/ml (CSS) (control 4.2 ng/ml; P < 0.01), while TGF-beta 2 levels were not elevated. Flow cytometry analysis showed TGF-beta 1 to be a potent translocation factor for PR3 comparable to other neutrophil-activating factors such as IL-8. PR3 membrane expression on primed PMN increased by up to 51% after incubation with TGF-beta 1. PR3 itself was revealed as a potent activator of latent TGF-beta, thus mediating bioeffects of this cytokine. These findings, together with other features of TGF-beta such as induction of angiogenesis and its strong chemotactic capacity, indicate that TGF-beta might serve as a proinflammatory factor in SV, especially in AAV.
Csernok
E
E
Department of Clinical Rheumatology, Medical University of Lübeck, Germany.
Szymkowiak
C H
CH
Mistry
N
N
Daha
M R
MR
Gross
W L
WL
Kekow
J
J
D019268:Antibodies, Antineutrophil Cytoplasmic; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001483:Base Sequence; D015267:Churg-Strauss Syndrome / Q000097:blood / Q000235:genetics / Q000276:immunology*; D003593:Cytoplasm / Q000276:immunology; D014890:Granulomatosis with Polyangiitis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016623:Ion Pumps / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology; D008969:Molecular Sequence Data; D053146:Myeloblastin; D010488:Polyarteritis Nodosa / Q000097:blood / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000276:immunology / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D016623:Ion Pumps; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D012697:Serine Endopeptidases; D053146:Myeloblastin