Role of transforming growth factor beta1 in microvascular endothelial cell apoptosis associated with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome.
Primary human microvascular endothelial cells (MVEC) of restricted lineage undergo apoptosis when exposed to plasma from patients with thrombotic thrombocytopenic purpura (TTP) and sporadic hemolytic-uremic syndrome (HUS). This reflects the pathology and tissue distribution of lesions in vivo. As extracellular matrix (ECM) is critical to MVEC survival, and cytokines which regulate ECM, such as transforming growth factor (TGF)-beta1, have been reported anecdotally to be altered in TTP/HUS, we examined the role of TGF-beta1 and two ECM proteins, fibronectin and thrombospondin (TSP), in these disorders. Levels of active TGF-beta1 were elevated in acute but not convalescent phases of TTP/sporadic HUS, as well as TTP associated with human immunodeficiency virus infection and use of the anti-platelet drug ticlopidine. MVEC from tissues susceptible to TTP-mediated apoptosis showed little active TGF-beta1 production when exposed to TTP plasmas. In contrast, pulmonary MVEC and large-vessel EC, which are resistant to TTP-linked pathology, showed marked induction of TGF-beta1 following TTP plasma exposure. Exogenous TGF-beta1 suppressed TTP plasma-mediated apoptosis in susceptible MVEC in association with blockade of cell entry into S phase. Soluble TSP, devoid of detectable bound TGF-beta1, had a similar effect, which paralleled its ability to induce TGF-beta1 production in MVEC. In vivo, TSP deposition was diminished markedly in involved tissues of TTP patients. These data highlight the role of TGF-beta1 and ECM in TTP and suggest that differential production of TGF-beta1 by MVEC may play a role in their sensitivity or resistance to TTP/sporadic HUS-mediated apoptosis in vitro and in vivo.
Mauro
M
M
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Kim
J
J
Costello
C
C
Laurence
J
J
D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology; D015658:HIV Infections / Q000150:complications; D006463:Hemolytic-Uremic Syndrome / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000098:blood supply; D009928:Organ Specificity; D014066:Palatine Tonsil / Q000098:blood supply; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D010976:Platelet Count; D011697:Purpura, Thrombotic Thrombocytopenic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000098:blood supply; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019699:Thrombospondins / Q000378:metabolism / Q000494:pharmacology; D013988:Ticlopidine / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000097:blood / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D016895:Culture Media, Serum-Free; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate; D013988:Ticlopidine