A recombinant IL-4-Pseudomonas exotoxin inhibits protein synthesis and overcomes apoptosis resistance in human CLL B cells.
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.
Kay
Neil E
NE
Mayo Clinic, Stabile 628, 200 First Street SW, Rochester, MN 55905, USA. kay.neil@mayo.edu
Bone
Nancy D
ND
Lee
Yean K
YK
Jelinek
Diane F
DF
Leland
Pamela
P
Battle
Traci E
TE
Frank
David A
DA
Puri
Raj K
RK
D017209:Apoptosis / Q000187:drug effects*; D001427:Bacterial Toxins / Q000494:pharmacology*; D005098:Exotoxins / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism
D001427:Bacterial Toxins; D005098:Exotoxins; D011500:Protein Synthesis Inhibitors; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D014157:Transcription Factors; C479467:interleukin-4-Pseudomonas exotoxin; D015847:Interleukin-4