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Blood, 1 January 2001, Vol. 97, No. 1, pp. 242-249
NEOPLASIA
Interleukin-6 dimers produced by endothelial cells inhibit
apoptosis of B-chronic lymphocytic leukemia cells
Ana Moreno,
María
Luisa Villar,
Carmen Cámara,
Rosario Luque,
Constantino Cespón,
Pedro González-Porqué,
Garbiñe Roy,
Javier López-Jiménez,
Alfredo Bootello, and
Ernesto Roldán Santiago
From the Servicios de Inmunología y
Hematología, Hospital Ramón y Cajal, Madrid, Spain.
Tumoral lymphocytes from patients with B-chronic lymphocytic
leukemia (B-CLL) are long-lived cells in vivo, but they die rapidly by
apoptosis in vitro. Here, it is reported that endothelial cells (ECs)
inhibit the apoptosis of B-CLL cells, as determined by 4 different flow
cytometric methods, and that this antiapoptotic effect is mediated
mainly by soluble factor(s), as can be deduced from the following
findings. First, EC-conditioned medium (ECCM) inhibited the apoptotic
rate in B-CLL to approximately 50% of control. Second, the
antiapoptotic effect mediated by EC/B-CLL cell contact was more
apparent than real; using a fluorescence-based phagocytosis assay, it
was demonstrated that this effect was due to the phagocytic capacity of
ECs, which internalized apoptotic cells. Third, the protective effect
of ECCM was associated neither with proliferation nor differentiation
signals. Fourth, the survival factor was a dimeric form of IL-6 because
anti-IL-6 antibodies completely neutralized the antiapoptotic effect
mediated not only by the crude ECCM but also by the 45- to 55-kd active
fractions obtained after gel filtration, which contained high levels of IL-6. These IL-6 dimers (IL-6D) were noncovalently
associated. Sixth, human recombinant IL-6D
(hrIL-6D) inhibited B-CLL apoptosis, whereas hrIL-6
monomers (hrIL-6M) did not. Binding and functional competition experiments showed not only that monomers and dimers had
similar affinity for the IL-6R, but also that hrIL-6M
inhibited the antiapoptotic activity of hrIL-6D. These data
suggest that IL-6D derived from ECs promote the survival of
B-CLL cells.
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