Proinflammatory cytokines as mediators of oxidative stress in fanconi anemia

Annarita Aiello Talamanca, Giuseppe Castello

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

The most important immune defect in Fanconi Anemia (FA) is pancytopenia. The immune status in FA patients is characterized by altered IgG, IgM and IgA serum levels, a relative increase of cytotoxic T cells, naïve T cells, and regulatory T cells, higher levels of proinflammatory cytokines, in particular TNF-α, TGF-β, (IL)-6, INF-γ and IL-1β (IL- 1β only in FA group A) and a lower number of Natural Killer (NK) cells compared to healthy donors. Excess TNF-α levels may affect Hematopoietic Stem Cell (HSC) function directly by impairing HSC survival, homing and proliferation, or indirectly by changing the bone marrow microenvironment that is critical for HSC homeostasis and function; in this way it contributes to disease progression in FA. TNF-α-induced senescence seems to be strictly correlated with the accumulation of Reactive Oxygen Species (ROS) and oxidative DNA damage. Moreover, loss of FA proteins could be responsible for an upregulation of the basal NF-κB transcriptional activity, and therefore of some of the genes regulated by this pathway, for example, pro-inflammatory cytokines. The redox-related pro-inflammatory state in FA cells has three important consequences: 1. the inhibition of HSC expansion; 2. increase of chromosomal instability predisposing to cancer; 3. the apoptosis activation in FA cells. In this chapter we discuss the links between two of the most important hallmarks of FA, namely inflammation and oxidative stress (OS), and possible implications for the use of antioxidants to stop the initiation and delay disease progression.

Original languageEnglish
Title of host publicationFanconi Anemia and Oxidative Stress: Mechanistic Background and Clinical Prospects
PublisherNova Science Publishers, Inc.
Pages109-119
Number of pages11
ISBN (Print)9781634638326, 9781634822978
Publication statusPublished - Apr 1 2015

Keywords

  • Hematopoietic stem cells
  • Inflammation
  • Interferon-γ
  • Reactive oxygen species
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Medicine(all)

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