Engagement of the leukocyte-associated Ig-like receptor-1 induces programmed cell death and prevents NF-kappaB nuclear translocation in human myeloid leukemias

Eur J Immunol. 2000 Oct;30(10):2751-8. doi: 10.1002/1521-4141(200010)30:10<2751::AID-IMMU2751>3.0.CO;2-L.

Abstract

Leukocyte-associated Ig-like receptor-1 (LAIR-1) is a surface molecule that functions as an inhibitory receptor on natural killer cells, T lymphocytes and monocytes. Here, we provide evidence that occupancy of LAIR-1 on human myelomonocytic leukemic cell lines inhibits proliferation and leads to programmed cell death (PCD), evaluated by propidium iodide staining and transmission electron microscopy. Interestingly, PCD elicited via LAIR-1 was not blocked by different caspase inhibitors, at variance with apoptosis induced via CD95/Fas, which was prevented by the caspase-1 and caspase-8 specific inhibitors. In addition, we show that the p65 subunit of the nuclear factor kappaB (NF-kappaB), constitutively expressed in the nucleus of these cell lines, was retained in the cytoplasm upon engagement of LAIR-1. This was evident already 8 h after LAIR-1 occupancy, when apoptosis was not yet detectable by fluorometric or ultrastructural analysis. Moreover, a reduction in inhibitor kappaBalpha phosphorylation was observed after LAIR-1 engagement. As blocking of NF-kappaB activation has been shown to rescue sensitivity to anti-cancer drugs in solid tumors, we suggest that LAIR-1 may represent a possible target for pharmacological approaches aimed to potentiate anti-leukemic therapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 1 / physiology
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / physiology
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Cell Nucleus / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA-Binding Proteins / metabolism
  • Drug Design
  • Fas Ligand Protein
  • Gene Expression Regulation, Leukemic* / drug effects
  • Humans
  • I-kappa B Proteins*
  • Leukemia, Myelomonocytic, Acute / genetics
  • Leukemia, Myelomonocytic, Acute / metabolism
  • Leukemia, Myelomonocytic, Acute / pathology*
  • Membrane Glycoproteins / physiology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / physiology*
  • Signal Transduction
  • Transcription Factor RelA
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • U937 Cells / drug effects
  • U937 Cells / metabolism
  • fas Receptor / physiology

Substances

  • Antibodies, Monoclonal
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • DNA-Binding Proteins
  • FASLG protein, human
  • Fas Ligand Protein
  • I-kappa B Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • NFKBIA protein, human
  • Neoplasm Proteins
  • Receptors, Immunologic
  • Transcription Factor RelA
  • fas Receptor
  • leukocyte-associated immunoglobulin-like receptor 1
  • NF-KappaB Inhibitor alpha
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases
  • Caspase 1