Interleukin-6 dimers produced by endothelial cells inhibit apoptosis of B-chronic lymphocytic leukemia cells

Tumoral lymphocytes from patients with B-chronic lymphocytic leukemia (B-CL L) 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 o f B-CLL cells, as determined by 4 different flow cytometric methods, and th at this antiapoptotic effect is mediated mainly by soluble factor(s), as ca n be deduced from the following findings. First, EC-conditioned medium (ECC M) inhibited the apoptotic rate in B-CLL to approximately 50% of control. S econd, the antiapoptotic effect mediated by EC/B-CLL cell contact was more apparent than real; using a fluorescence-based phagocytosis assay, it was d emonstrated that this effect was due to the phagocytic capacity of ECs, whi ch internalized apoptotic cells. Third, the protective effect of ECCM was a ssociated neither with proliferation nor differentiation signals, Fourth, t he survival factor was a dimeric form of IL-6 because anti-IL-6 antibodies completely neutralized the antiapoptotic effect mediated not only by the cr ude ECCM but also by the 45- to 55-kd active fractions obtained after gel f iltration, which contained high levels of IL-6, These IL-6 dimers (IL-6(D)) were noncovalently associated, Sixth, human recombinant IL-6(D) (hrIL-6(D) ) inhibited B-CLL apoptosis, whereas hrIL-6 monomers (hrIL-6(M)) did not. B inding and functional competition experiments showed not only that monomers and dimers had similar affinity for the IL-6R, but also that hrIL-6(M) inh ibited the antiapoptotic activity of hrIL-60. These data suggest that IL-6( D), derived from ECs promote the survival of B-CLL cells. (C) 2001 by The A merican Society of Hematology.