INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA SUPPRESS BOTH EARLY AND LATE STAGES OF HEMATOPOIESIS AND INDUCE PROGRAMMED CELL-DEATH

被引：193

作者：

SELLERI, C ^{[1
]}

SATO, T ^{[1
]}

ANDERSON, S ^{[1
]}

YOUNG, NS ^{[1
]}

MACIEJEWSKI, JP ^{[1
]}

机构：

[1] NHLBI, HEMATOL BRANCH, BETHESDA, MD 20892 USA

来源：

JOURNAL OF CELLULAR PHYSIOLOGY | 1995年 / 165卷 / 03期

关键词：

D O I：

10.1002/jcp.1041650312

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Increased expression of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in bone marrow failure disorders suggests a possible pathophysiologic role of these cytokines in disease. In this study, we tested the action of TNF-alpha and IFN-gamma on phenotypically and functionally defined stages of hematopoietic development using highly purified progenitor cell populations assayed in standardized culture systems. We hypothesized that the inhibitory effects of IFN-gamma and TNF-alpha might be related to the induction of programmed cell death. In methylcellulose colony assays, IFN-gamma and TNF-alpha inhibited the growth of early hematopoietic cells, including committed CD34(+)CD38(+) progenitor cells and phenotypically less mature CD34(+)CD38(-) cells, with 50% decreased colony formation occurring in the range of 750-1,000 U/ml of lFN-gamma and 10-15 ng/ml of TNF-alpha. More potent suppressive effects were observed in cultures supplemented with the combination of both cytokines than in cultures treated with IFN-gamma or TNF-alpha alone. When used at these concentrations, IFN-gamma and TNF-alpha inhibited growth of CD34(+) -enriched long-term culture-initiating cells by 88% and 68%, respectively. IFN-gamma and TNF-alpha triggered apoptosis of total bane marrow and CD34(+) cells, recognized by the presence of a characteristic pattern of DNA degradation after low molecular weight DNA extraction, and by detection of apoptotic cells by the in situ terminal deoxynucleotidyl transferase assay. We speculate that chronic exposure of hematopoietic tissue to TNF-alpha and IFN-gamma in vivo may result in broad depletion of the stem and progenitor cell pools. Death of these cells due to apoptosis rather than transient inhibition of proliferation maybe responsible for long-lasting hematologic consequences. (C) 1995 Wiley-Liss, Inc.

引用

页码：538 / 546

页数：9

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