Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor α- induced apoptosis: Evidence for an alternate biological function

Joanne L. Dickinson, Edna J. Bates, Antonio Ferrante, Toni M. Antalis

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Abstract

Plasminogen activator inhibitor type 2 (pAI-2) is a serine proteinase inhibitor or serpin that is a major product of macrophages in response to endotoxin and inflammatory cytokines. We have explored the role of PAI-2 in apoptotic cell death initiated by tumor necrosis factor a (TNF). HeLa cells stably transfected with PAI-2 cDNA were protected from TNF-induced apoptosis, whereas cells transfected with antisense PAI-2 cDNA, a control gene, or the plasmid vector alone remained susceptible. The level of PAI-2 expressed by different HeLa cell clones was inversely correlated with their sensitivity to TNF. Loss of TNF sensitivity was not a result of loss of TNF receptor binding. In contrast, PAI-2 expression did not confer protection against apoptosis induced by ultraviolet or ionizing radiation. The serine proteinase urokinase-type plasminogen activator was not demonstrated to be the target of pAI-2 action. The P1-Arg amine acid residue of PAI-2 was determined to be required for protection, because cells expressing PAI-2 with an Ala in this position were not protected from TNF-mediated cell death. The results suggest that intracellular PAI-2 might he an important factor in regulating cell death in TNF-mediated inflammatory processes through inhibition of a proteinase involved in TNF-induced apoptosis.

Original languageEnglish
Pages (from-to)27894-27904
Number of pages11
JournalJournal of Biological Chemistry
Volume270
Issue number46
DOIs
Publication statusPublished or Issued - 1995

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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