title: 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.
abstract: Our previous studies using in situ end labeling (ISEL) of fragmented DNA 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 synthesis of interleukin-1 beta (IL-1 beta) in 4 hour cultures of density separated BM aspirate mononuclear (BMAM) cells from MDS patients as compared to the cultures of normal BM from healthy donors or lymphoma patients (1.7 +/- 0.37 pg/10(5) cells, n = 29 v 0.42 +/- 0.24 pg/10(5) cells, n = 11, respectively, P = .049). Further, these amounts of IL-1 beta 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 correlation between the two (r = .091, n = 12, P = .779). No significant correlation was found between the amounts of IL-1 beta and % S-phase cells (labeling index; LI%) in MDS determined in BM biopsies using immunohistochemistry following in vivo infusions of iodo- and/or bromodeoxyuridine. Neither anti-IL-1 beta antibody nor IL-1 receptor antagonist blocked the apoptotic death of BMAM cells in 4 hour cultures (n = 5) determined by ISEL (apoptotic index; AI%), 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 mumol/L in 5/6 MDS cases studied (AI% = 2.99 +/- 0.30 in controls v 1.58 +/- 0.40 with ICE-inhibitor, P = .05) and also reduced the levels of active IL-1 beta synthesized (5.59 +/- 2.63 v 2.24 +/- 0.93 pg/10(6) cells, respectively). In normal cells, neither IL-1 blockers nor the ICE inhibitor showed any effect on the marginal increase in apoptosis observed 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.
authors.affiliation: Rush Cancer Institute, Rush-Presbyterian-St Luke's Medical Center, Chicago, IL 60612, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Mundle
authors.forename: P
authors.initials: P
authors.lastname: Venugopal
authors.forename: J D
authors.initials: JD
authors.lastname: Cartlidge
authors.forename: D V
authors.initials: DV
authors.lastname: Pandav
authors.forename: L
authors.initials: L
authors.lastname: Broady-Robinson
authors.forename: S
authors.initials: S
authors.lastname: Gezer
authors.forename: E L
authors.initials: EL
authors.lastname: Robin
authors.forename: S R
authors.initials: SR
authors.lastname: Rifkin
authors.forename: M
authors.initials: M
authors.lastname: Klein
authors.forename: D E
authors.initials: DE
authors.lastname: Alston
authors.forename: B M
authors.initials: BM
authors.lastname: Hernandez
authors.forename: D
authors.initials: D
authors.lastname: Rosi
authors.forename: S
authors.initials: S
authors.lastname: Alvi
authors.forename: V T
authors.initials: VT
authors.lastname: Shetty
authors.forename: S A
authors.initials: SA
authors.lastname: Gregory
authors.forename: A
authors.initials: A
authors.lastname: Raza
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001853:Bone Marrow / Q000473:pathology*; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000276:immunology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004261:DNA Replication; D010450:Endopeptidases / Q000502:physiology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000201:enzymology* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D015853:Cysteine Proteinase Inhibitors; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D009842:Oligopeptides; D012795:Sialoglycoproteins; C096429:L 709049; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D020170:Caspase 1