INDICATION OF AN INVOLVEMENT OF INTERLEUKIN-1-BETA CONVERTING ENZYME-LIKE PROTEASE IN INTRAMEDULLARY APOPTOTIC CELL-DEATH IN THE BONE-MARROW OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES

Our previous studies using in situ end labeling (ISEL) of fragmented D NA revealed extensive apoptotic cell death in the bone marrows (BM) of patients with myelodysplastic syndromes (MDS) involving both stromal and hematopoietic cells, In the present report we show greater synthes is of interleukin-1 beta (IL-1 beta) in 4 hour cultures of density sep arated BM aspirate mononuclear (BMAM) cells from MDS patients as compa red to the cultures of normal BM from healthy donors or lymphoma patie nts (1.7 +/- 0.37 pg/10(6) cells, n = 29 v 0.42 +/- 0.24 pg/10(6) cell s, n = 11, respectively, P = .049). Further, these amounts of IL-1 bet a in MDS showed a significant correlation with the extent of apoptosis detected by ISEL in corresponding plastic embedded BM biopsies (r = . 480, n = 30, P = .007), In contrast normal BMs did not show any correl ation between the two (r = .091, n = 12, P = .779), No significant cor relation was found between the amounts of IL-1 beta and % S-phase cell s (labeling index: Ll%) in MDS determined in BM biopsies using immunoh istochemistry following in vivo infusions of iodo- and/or bromodeoxyur idine. Neither anti-IL-lp antibody nor IL-l receptor antagonist blocke d the apoptotic death of BMAM cells in 4 hour cultures (n = 5) determi ned by ISEL (apoptotic index; Al%), although the latter led to a dose- dependent accumulation of active IL-1 beta in the culture supernatants . On the other hand, a specific tetrapetide-aldehyde inhibitor of ICE significantly retarded the apoptotic death of BMAM cells at 1 mu mol/L in 5/6 MDS cases studied (Al% = 2.99 +/- 0.30 in controls v 1.58 +/- 0.40 with ICE-inhibitor, P = .05) and also reduced the levels of activ e IL-1 beta synthesized (5.59 +/- 2.63 v 2.24 +/- 0.93 pg/10(6) cells, respectively). In normal cells, neither IL-l blockers nor the ICE inh ibitor showed any effect on the marginal increase in apoptosis observe d in 4 hour cultures. Our data thus suggest a possible involvement of an ICE-like protease in the intramedullary apoptotic cell death in the BMs of MDS patients. (C) 1996 by The American Society of Hematology.