Lack of 'tissue' transglutaminase protein cross-linking leads to leakage of macromolecules from dying cells: Relationship to development of autoimmunity in MRLlpr/lpr mice

Lucia Piredda, Alessandra Amendola, Vittorio Colizzi, Peter J.A. Davies, Maria Grazia Farrace, Maurizio Fraziano, Vittorio Gentile, Ivan Uray, Mauro Piacentini, Laszlo Fesus

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Genetic defects of the CD95 (Fas/Apo-1) receptor/ligand system, has recently been involved in the development of human and murine autoimmunity. We investigated whether a deregulation of the 'tissue' transglutaminase (tTG), a multifunctional enzyme which is part of the molecular program of apoptosis, may act as a cofactor in the development of autoimmunity. We found that MRLlpr/lpr, which are characterized by a defect in the CD95 receptor and suffer of a severe systemic lupus erythematosus-like disease, produce large amounts of circulating tTG autoantibodies. This phenomenon is paralleled by an abnormal accumulation of an inactive enzyme protein in the accessory cells of lymphoid organs. To investigate the molecular mechanisms by which tTG inhibition may contribute to the development of autoimmunity we generated a cell culture model system consisting of L929 cells stably transfected with a full length tTG cDNA. When L929 cells were killed by Tumor Necrosis Factor α (TNFα) a pronounced release of DNA and Lactate Dehydrogenase (LDH) was observed. Overexpression of tTG in these cells largely prevented the leakage of macromolecules determined by TNFα treatment, an effect which is abolished by inactivating the enzyme cross-linking activity by a synthetic inhibitor. These in vitro observations provided the basis to explain the increased levels of plasmatic LDH we detected in MRLlpr/lpr mice. These data suggest that lack of an active tTG may represent a cofactor in the development of autoimmunity.

Original languageEnglish
Pages (from-to)463-472
Number of pages10
JournalCell Death and Differentiation
Volume4
Issue number6
DOIs
Publication statusPublished - Jan 1 1997

Keywords

  • Apoptosis
  • Autoantibody
  • Follicular dendritic cells
  • LDH
  • Lymph nodes
  • TNFα

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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