Cytokine modulation of nuclear factor-kappaB activity in B-chronic lymphocytic leukemia

Abstract

Objective: Dysregulation of the apoptotic mechanisms plays a key role in the accumulation of malignant B-chronic lymphocytic leukemia (B-CLL) cells. The transcription nuclear factor (NF)-kappaB is important for cell survival by regulating the expression of anti-apoptotic genes. Several cytokines can modulate leukemic growth and apoptosis in B-CLL. The aim of this study was to determine whether cytokine-mediated regulation of apoptosis occurs via modulation of NF-kappaB activity in peripheral blood mononuclear cells from B-CLL patients.

Patients and methods: We evaluated NF-kappaB activity in peripheral blood mononuclear cells from 15 untreated B-CLL patients and 11 controls in resting conditions and in the presence of phorbol-12-myristate-13-acetate (PMA) and different cytokines by electrophoretic mobility shift assay. Apoptosis was studied by spectrophotometric analysis of DNA fragmentation.

Results: We found a constitutive high NF-kappaB activity not induced by PMA in B-CLL patients, in contrast with a normal inducible NF-kappaB activity in controls. In B-CLL cultures, addition of interleukin (IL)-4 and IL-13 increased, whereas transforming growth factor (TGF)-beta reduced NF-kappaB activity compared with unstimulated cultures. Accordingly, IL-4 and IL-13 decreased, whereas TGF-beta increased DNA fragmentation compared with unstimulated cultures. IL-13 and IL-4 production was increased, whereas TGF-beta was reduced in PMA-stimulated and unstimulated cultures from B-CLL patients compared with controls.

Conclusions: B-CLL patients have a constitutive high NF-kappaB activity, which is modulated by cytokines. In particular, TGF-beta displays a pro-apoptotic activity, whereas IL-4 and IL-13 have opposite effects. These cytokine alterations could be responsible for a positive autocrine circuit that maintains leukemic cells in a pre-apoptotic state.