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


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.
Zaninoni
Anna
A
Dipartimento di Ematologia, IRCCS Ospedale Maggiore di Milano, Milan, Italy.
Imperiali
Francesca Guia
FG
Pasquini
Cristina
C
Zanella
Alberto
A
Barcellini
Wilma
W
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D016207:Cytokines / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D016207:Cytokines; D018793:Interleukin-13; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D013755:Tetradecanoylphorbol Acetate