INTERLEUKIN-8 INDUCES THE ACCUMULATION OF B-CELL CHRONIC LYMPHOCYTIC-LEUKEMIA CELLS BY PROLONGING SURVIVAL IN AN AUTOCRINE FASHION

Several cytokines have been suggested to play a regulatory action on t he neoplastic clone of patients with B-cell chronic lymphocytic leukem ia (B-CLL) by interfering in the differentiation, proliferation, or de ath/survival pathways. Interleukin-8 (IL-8) is a chemoattractant prote in constitutively expressed at the mRNA level and released by B-CLL ce lls. In view of the presence of the IL-8 receptor mRNA and of specific IL-8 binding, confirmed also by Scatchard analysis using I-125-IL-8, the study was extended to evaluate the possible regulatory role of thi s cytokine on B-CLL cells. IL-8 failed to show any in vitro proliferat ive effect on leukemic B-CLL cells. By contrast, the propidium iodide (PI) staining of the DNA content showed that IL-8 could prolong the su rvival of resting B-CLL cells in 11 of 16 cases studied. In the remain ing 5 cases, 90.6% +/- 4.39% SD of the cells after culture remained vi able and IL-8 could exert a significant death protection action after pretreatment with 10(-4) mol/L hydrocortisone, which reduced the perce ntage of viable B-CLL cells. The dose range of IL-8 capable of inducin g the prolonging survival effect is comparable with the levels of IL-8 released constitutively by B-CLL cells, indicating that the death pro tection action is exerted at physiologic doses. The in vitro rescue fr om death induced by IL-8 is reflected by an increased expression of bc l-2 mRNA in B-CLL cases incubated in the presence of IL-8. These findi ngs were further confirmed at the protein level, because in B-CLL cell s that displayed a bimodal bcl-2 intracytoplasmatic protein expression IL-8 was capable of upmodulating the bcl-2(high) expression peak. The potential autocrine regulatory action exerted by IL-8 is supported by the evidence that exogenous IL-8 can upregulate IL-8 mRNA in B-CLL ce lls. These results, together with the demonstration that antibody-medi ated neutralization of endogenous IL-8 could induce a significant in v itro reduction in the number of living cells, further support the hypo thesis that, in B-CLL, the physiologic doses of IL-8 released constitu tively by the leukemic clone may play an autocrine role in the process of cell accumulation characteristic of this disease. (C) 1996 by The American Society of Hematology.