Immunomodulatory Properties and Molecular Effects in Inflammatory Diseases of Low-Dose X-Irradiation

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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.

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Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.

K. Rothkamm, M Löbrich (2003)

DNA double-strand breaks (DSBs) are generally accepted to be the most biologically significant lesion by which ionizing radiation causes cancer and hereditary disease. However, no information on the induction and processing of DSBs after physiologically relevant radiation doses is available. Many of the methods used to measure DSB repair inadvertently introduce this form of damage as part of the methodology, and hence are limited in their sensitivity. Here we present evidence that foci of gamma-H2AX (a phosphorylated histone), detected by immunofluorescence, are quantitatively the same as DSBs and are capable of quantifying the repair of individual DSBs. This finding allows the investigation of DSB repair after radiation doses as low as 1 mGy, an improvement by several orders of magnitude over current methods. Surprisingly, DSBs induced in cultures of nondividing primary human fibroblasts by very low radiation doses (approximately 1 mGy) remain unrepaired for many days, in strong contrast to efficient DSB repair that is observed at higher doses. However, the level of DSBs in irradiated cultures decreases to that of unirradiated cell cultures if the cells are allowed to proliferate after irradiation, and we present evidence that this effect may be caused by an elimination of the cells carrying unrepaired DSBs. The results presented are in contrast to current models of risk assessment that assume that cellular responses are equally efficient at low and high doses, and provide the opportunity to employ gamma-H2AX foci formation as a direct biomarker for human exposure to low quantities of ionizing radiation.

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A clinical perspective of IL-1β as the gatekeeper of inflammation.

Charles Dinarello (2011)

An expanding spectrum of acute and chronic non-infectious inflammatory diseases is uniquely responsive to IL-1β neutralization. IL-1β-mediated diseases are often called "auto-inflammatory" and the dominant finding is the release of the active form of IL-1β driven by endogenous molecules acting on the monocyte/macrophage. IL-1β activity is tightly controlled and requires the conversion of the primary transcript, the inactive IL-1β precursor, to the active cytokine by limited proteolysis. Limited proteolysis can take place extracellularly by serine proteases, released in particular by infiltrating neutrophils or intracellularly by the cysteine protease caspase-1. Therefore, blocking IL-1β resolves inflammation regardless of how the cytokine is released from the cell or how the precursor is cleaved. Endogenous stimulants such as oxidized fatty acids and lipoproteins, high glucose concentrations, uric acid crystals, activated complement, contents of necrotic cells, and cytokines, particularly IL-1 itself, induce the synthesis of the inactive IL-1β precursor, which awaits processing to the active form. Although bursts of IL-1β precipitate acute attacks of systemic or local inflammation, IL-1β also contributes to several chronic diseases. For example, ischemic injury, such as myocardial infarction or stroke, causes acute and extensive damage, and slowly progressive inflammatory processes take place in atherosclerosis, type 2 diabetes, osteoarthritis and smoldering myeloma. Evidence for the involvement of IL-1β and the clinical results of reducing IL-1β activity in this broad spectrum of inflammatory diseases are the focus of this review. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production.

A Ding, C F Nathan, D J Stuehr (1988)

The capacity of 12 cytokines to induce NO2- or H2O2 release from murine peritoneal macrophages was tested by using resident macrophages, or macrophages elicited with periodate, casein, or thioglycollate broth. Elevated H2O2 release in response to PMA was observed in resident macrophages after a 48-h incubation with IFN-gamma, TNF-alpha, TNF-beta, or CSF-GM. Of these, only IFN-gamma induced substantial NO2- secretion during the culture period. The cytokines inactive in both assays under the conditions tested were IL-1 beta, IL-2, IL-3, IL-4, IFN-alpha, IFN-beta, CSF-M, and transforming growth factor-beta 1. Incubation of macrophages with IFN-gamma for 48 h in the presence of LPS inhibited H2O2 production but augmented NO2- release, whereas incubation in the presence of the arginine analog NG-monomethylarginine inhibited NO2- release but not H2O2 production. Although neither TNF-alpha nor TNF-beta induced NO2- synthesis on its own, addition of either cytokine together with IFN-gamma increased macrophage NO2- production up to six-fold over that in macrophages treated with IFN-gamma alone. Moreover, IFN-alpha or IFN-beta in combination with LPS could also induce NO2- production in macrophages, as was previously reported for IFN-gamma plus LPS. These data suggest that: 1) tested as a sole agent, IFN-gamma was the only one of the 12 cytokines capable of inducing both NO2- and H2O2 release; 2) the pathways leading to secretion of H2O2 and NO2- are independent; 3) either IFN-gamma and TNF-alpha/beta or IFN-alpha/beta/gamma and LPS can interact synergistically to induce NO2- release.

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Author and article information

Journal

Journal ID (nlm-ta): Front Oncol

Journal ID (iso-abbrev): Front Oncol

Journal ID (publisher-id): Front. Oncol.

Title: Frontiers in Oncology

Publisher: Frontiers Research Foundation

ISSN (Electronic): 2234-943X

Publication date (Electronic preprint): 02 August 2012

Publication date (Electronic): 25 September 2012

Publication date Collection: 2012

Volume: 2

Electronic Location Identifier: 120

Affiliations

[1] ¹simpleDepartment of Radiotherapy and Oncology, University Hospital of Frankfurt, Johann Wolfgang-Goethe Universität Frankfurt am Main, Germany

[2] ²simpleDepartment of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg Erlangen, Germany

[3] ³simpleDepartment of Radiotherapy and Radiation Oncology, University of Rostock Rostock, Germany

[4] ⁴simpleDepartment of Radiotherapy, Clinical Center Bayreuth Bayreuth, Germany

[5] ⁵simpleStrahlenzentrum Hamburg Medizinisches Versorgungszentrum Hamburg, Germany

Author notes

Edited by: Gabriele Multhoff, Technische Universität München, Germany

Reviewed by: Deborah Stroka, University of Bern, Switzerland; Bernd Kaina, University Mainz, Germany

*Correspondence: Franz Rödel, Department of Radiation Therapy and Oncology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. e-mail: franz.roedel@ 123456kgu.de

^†Franz Rödel and Benjamin Frey have contributed equally to this work.

This article was submitted to Frontiers in Cancer Molecular Targets and Therapeutics, a specialty of Frontiers in Oncology.

Article

DOI: 10.3389/fonc.2012.00120

PMC ID: 3457026

PubMed ID: 23057008

SO-VID: b65d2917-39a3-4518-84bd-242e71f5c069

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

History

Date received : 03 July 2012

Date accepted : 03 September 2012

Page count

Figures: 1, Tables: 1, Equations: 0, References: 94, Pages: 9, Words: 8678

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Immunomodulatory Properties and Molecular Effects in Inflammatory Diseases of Low-Dose X-Irradiation

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Most cited references 65

Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.

A clinical perspective of IL-1β as the gatekeeper of inflammation.

Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production.

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