TNF-α-induced programmed cell death in the pathogenesis of acquired aplastic anemia

Abstract

The mechanism of acquired aplastic anemia (AA), a bone marrow hematopoiesis failure disease, has not been fully understood. TNF-α is a pleiotropic cytokine involved in cell proliferation, differentiation and death, and inflammation through binding to specific receptors on cell membranes. Aberrant secretion of TNF-α contributes to a number of human diseases, including tumor development and inflammation. TNF-α is also an important negative regulator of hematopoiesis. Over-expression of TNF-α not only directly inhibits the proliferation and differentiation of hematopoietic cells, but also initiates the intracellular death pathway to induce hematopoietic cell death, leading to bone marrow hematopoiesis failure. In this review, we summarize the mechanisms underlying extrinsic apoptosis and necroptosis of hematopoietic cells induced by TNF-α, and discuss the role of TNF-α-induced programmed cell death in the pathogenesis of acquired AA.

Keywords:

• acquired aplastic anemia
• caspase-dependent apoptosis
• caspase-independent necroptosis
• cytokines
• tumor necrosis factor-α

Financial & competing interests disclosure

This research was funded by the Public Welfare Technology Application Research Project of Zhejiang Province under Grant No. 2015C37122,Zhejiang, China; the Science and Technology Program Project of Taizhou under Grant No. 1301ky19, Zhejiang, China; the National Natural Science Foundation of China under Grant No. 81373139; and Zhejiang Provincial Natural Science Foundation of China under Grant No. LY12C05002, Zhejiang, China. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• TNF-α concentrations above a certain level can not only directly inhibit the proliferation and differentiation of hematopoietic cells but they can also initiate the intracellular death signal transduction pathway to induce hematopoietic cell death by binding to specific receptor on the cell membrane.

• TNF-α-mediated apoptosis is a main pathological process in acquired AA. The initiation of uncontrolled apoptosis in hematopoietic precursor cells may be one of the important causes of hematopoietic failure.

• TNF-α-mediated necroptosis is a newly discovered mode of cell death that is involved in the pathophysiological process of numerous diseases.

• In addition, it has been reported that the TNF-α-mediated necroptosis pathway may be involved in the development of bone marrow failure syndrome in Tak1 (−/−) mice.

• The role of TNF-α-mediated necroptosis in the pathogenesis of acquired AA deserves further investigation.

Notes