A recombinant IL-4-Pseudomonas exotoxin inhibits protein synthesis and overcomes apoptosis resistance in human CLL B cells

Leuk Res. 2005 Sep;29(9):1009-18. doi: 10.1016/j.leukres.2004.11.025. Epub 2005 Apr 12.

Abstract

We have determined that CLL B cells consistently express type 3 membrane receptors for the Th2-derived cytokine IL-4 (IL-4R). Furthermore, when added to CLL B cells, IL-4 induces increased apoptosis resistance, increased protein synthesis in CLL B cells and rapid onset activation of STAT1, STAT5 and STAT6. Since the IL-4-IL-4R pathway is intact in CLL B cells and is related to apoptosis resistance, we considered whether we could target this pathway. A recombinant IL-4 Pseudomonas exotoxin fusion protein (IL-4 PE), known to bind to IL-4R, was incubated with CLL B cells. IL-4 PE (10 ng/ml) cultured with CLL B cells resulted in an increase of apoptosis/death from mean levels of 46.6+/-7.0 of non-exposed cells to 69+/-8.6 (n=6). By measuring in vitro protein synthesis, two predominant patterns of sensitivity were observed. In one, CLL B cell clones (n=4) were found to be extremely sensitive to IL-4 PE (IC50's range=6-25 ng/ml). In the second, low concentrations of IL-4 PE induced agonist activity while increasing concentrations induced cytotoxicity in 6 of 21 patient-derived cells. These studies suggest that the IL-4R, on B-CLL cells, can serve as a unique molecular target for directing cytotoxic agents in the therapy of B-CLL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects*
  • Bacterial Toxins / pharmacology*
  • Exotoxins / pharmacology*
  • Flow Cytometry
  • Humans
  • Interleukin-4 / pharmacology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Protein Synthesis Inhibitors / pharmacology*
  • Receptors, Interleukin-4 / genetics
  • Receptors, Interleukin-4 / metabolism
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / metabolism

Substances

  • Bacterial Toxins
  • Exotoxins
  • Protein Synthesis Inhibitors
  • Receptors, Interleukin-4
  • Recombinant Proteins
  • Transcription Factors
  • interleukin-4-Pseudomonas exotoxin
  • Interleukin-4