Influence of CD40 ligation on survival and apoptosis of B-CLL cells in vitro.
Modulation of signal transduction pathways represents a promising approach for altering the biological behavior of hematopoetic malignancies. The cells of chronic lymphocytic leukemia were treated in vitro with CD40-ligand or IL-4 to explore their effects on survival and sensitivity to apoptosis induced by Fluda. The expression of G1 cell cycle regulatory proteins was also measured. Stimulation via CD40-CD40L resulted in increased viability, as did stimulation with IL-4. A combination of the two stimulators (CD40L plus IL-4) induced increased expression of cyclins D3 and E, pRb phosphorylation and downregulated p27. Cdk2 and Cdk4 activities were not detected. It seems that this combination induced also some progression in the cell cycle. Furthermore, Fluda-induced apoptosis was not prevented by CD40L, IL-4, or a combination of both agents, although a delay in the onset of apoptosis was observed. Taken together, these results support the view that CD40L and IL-4 sustain B-cell chronic lymphocytic leukemia (B-CLL) survival by different pathways and their synergistic action might induce cell cycle progression in B-CLL. The exposure of B-CLL to CD40L, IL-4 or both did not impair the sensitivity of B-CLL to Fluda. CD40L and IL-4 postponed apoptosis induced by Fluda, depending on a fashion of administration.
Grdisa
Mira
M
Departement d'Hematologie et d'Oncologie Medicale, Hopital Hotel Dieu, Paris, France. grdisa@irb.hr
D017209:Apoptosis; D019013:CD40 Antigens / Q000378:metabolism* / Q000502:physiology; D023201:CD40 Ligand / Q000494:pharmacology; D002470:Cell Survival; D056743:Cyclin D3; D019927:Cyclin E / Q000187:drug effects; D016213:Cyclins / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D015448:Leukemia, B-Cell / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction
C534696:CCND3 protein, human; D019013:CD40 Antigens; D056743:Cyclin D3; D019927:Cyclin E; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein; C413374:p27 antigen; D023201:CD40 Ligand; D015847:Interleukin-4