Immunomodulatory properties and molecular effects in inflammatory diseases of low-dose x-irradiation

Franz Rödel, Benjamin Frey, Katrin Manda, Guido Hildebrandt, Stephanie Hehlgans, Ludwig Keilholz, M Heinrich Seegenschmiedt, Udo S Gaipl, Claus Rödel, Franz Rödel, Benjamin Frey, Katrin Manda, Guido Hildebrandt, Stephanie Hehlgans, Ludwig Keilholz, M Heinrich Seegenschmiedt, Udo S Gaipl, Claus Rödel

Abstract

Inflammatory diseases are the result of complex and pathologically unbalanced multicellular interactions. For decades, low-dose X-irradiation therapy (LD-RT) has been clinically documented to exert an anti-inflammatory effect on benign diseases and chronic degenerative disorders. By contrast, experimental studies to confirm the effectiveness and to reveal underlying cellular and molecular mechanisms are still at their early stages. During the last decade, however, the modulation of a multitude of immunological processes by LD-RT has been explored in vitro and in vivo. These include leukocyte/endothelial cell adhesion, adhesion molecule and cytokine/chemokine expression, apoptosis induction, and mononuclear/polymorphonuclear cell metabolism and activity. Interestingly, these mechanisms display comparable dose dependences and dose-effect relationships with a maximum effect in the range between 0.3 and 0.7 Gy, already empirically identified to be most effective in the clinical routine. This review summarizes data and models exploring the mechanisms underlying the immunomodulatory properties of LD-RT that may serve as a prerequisite for further systematic analyses to optimize low-dose irradiation procedures in future clinical practice.

Keywords: discontinuous dose dependency; immune modulation; inflammation; low-dose radiation therapy.

Figures

Figure 1
Figure 1
Actual model on the modulation of inflammatory cell activity and factors involved in the anti-inflammatory effect of LD-RT (<1 Gy). Irradiation resulted in a hampered adhesion of peripheral blood mononuclear cells (PBMC) to the endothelium, due to the secretion of the anti-inflammatory cytokine transforming growth factor β1 (TGF-β1), a decreased expression of E-selectin on the surfaces of endothelial cells, a local increase of apoptosis, and the proteolytic shedding of L-selectin from PBMC. In stimulated macrophages a diminished activity of the inducible nitric oxide synthase (iNOS) in line with reduced levels of nitric oxide (NO), a lowered production of reactive oxygen species (ROS), and a diminished secretion of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) may contribute to local anti-inflammatory effects. Moreover, polymorphonuclear cells (PMN) respond to low-dose exposure with a locally increased rate of apoptosis, a hampered secretion of CCL20 chemokine and alterations in signal transduction pathways p38 mitogen activated protein kinase (MAPK) and protein kinase B (AKT).

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