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Relationship: 1903


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased pro-inflammatory mediators leads to Increase in RONS

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Increased DNA damage leading to increased risk of breast cancer adjacent High Not Specified Jessica Helm (send email) Under development: Not open for comment. Do not cite Under Development
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer adjacent High Not Specified Jessica Helm (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Pro-inflammatory mediators increase reactive oxygen and nitrogen species (RONS).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility is High. Inflammation is commonly understood to generate RONS via inflammatory signaling and activated immune cells.

Empirical Support is High. Signals arising from inflammation can be both pro- and anti-inflammatory, and both can have effects on RONS and downstream key events. Multiple inflammation-related factors increase RONS or oxidative damage, and ionizing radiation increases both inflammation-related signaling and RONS or oxidative damage over the same time points. Interventions to reduce inflammation also reduce RONS. The dose-dependence response to stressors is generally consistent between the two key events, although this is based on a small number of studies with some conflicting evidence.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Biological Plausibility is High. Inflammation is commonly understood to generate RONS via inflammatory signaling and activated immune cells (Zhao and Robbins 2009; Ratikan, Micewicz et al. 2015; Blaser, Dostert et al. 2016). Inflammation-related signals contributing to RONS include the cytokines TNF-a, IL1, and INF and the JNK/MAPK pathway (Bubici, Papa et al. 2006; Yang, Elner et al. 2007; Blaser, Dostert et al. 2016), as well as neutrophil and macrophage immune cells (Jackson, Gajewski et al. 1989; Stevens, Bucurenci et al. 1992; Fan, Li et al. 2007; Lorimore, Chrystal et al. 2008; Rastogi, Boylan et al. 2013; Weigert, von Knethen et al. 2018).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

RONS activates or is essential to many inflammatory pathways including TGF-β  (Barcellos-Hoff and Dix 1996; Jobling, Mott et al. 2006), TNF (Blaser, Dostert et al. 2016), Toll-like receptor (TLR) (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006; Miller, Goodson et al. 2017; Cavaillon 2018), and NF-kB signaling (Gloire, Legrand-Poels et al. 2006; Morgan and Liu 2011). These interactions principally involve ROS, but RNS can indirectly activate TLRs and possibly NF-kB.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help

Ameziane-El-Hassani, R., M. Talbot, et al. (2015). "NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation." Proceedings of the National Academy of Sciences of the United States of America 112(16): 5051-5056.

Asanuma, M., S. Nishibayashi-Asanuma, et al. (2001). "Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals." J Neurochem 76(6): 1895-1904.

Azimzadeh, O., H. Scherthan, et al. (2011). "Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation." Proteomics 11(16): 3299-3311.

Azimzadeh, O., W. Sievert, et al. (2015). "Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction." J Proteome Res 14(2): 1203-1219.

Black, A. T., M. K. Gordon, et al. (2011). "UVB light regulates expression of antioxidants and inflammatory mediators in human corneal epithelial cells." Biochem Pharmacol 81(7): 873-880.

Blaser, H., C. Dostert, et al. (2016). "TNF and ROS Crosstalk in Inflammation." Trends in cell biology 26(4): 249-261.

Bubici, C., S. Papa, et al. (2006). "Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance." Oncogene 25(51): 6731-6748.

Chai, Y., R. K. Lam, et al. (2013). "Radiation-induced non-targeted response in vivo: role of the TGFbeta-TGFBR1-COX-2 signalling pathway." Br J Cancer 108(5): 1106-1112.

Dickey, J. S., B. J. Baird, et al. (2012). "Susceptibility to bystander DNA damage is influenced by replication and transcriptional activity." Nucleic acids research 40(20): 10274-10286.

Dickey, J. S., B. J. Baird, et al. (2009). "Intercellular communication of cellular stress monitored by gamma-H2AX induction." Carcinogenesis 30(10): 1686-1695.

Fan, J., Y. Li, et al. (2007). "Hemorrhagic shock induces NAD(P)H oxidase activation in neutrophils: role of HMGB1-TLR4 signaling." J Immunol 178(10): 6573-6580.

Fehsel, K., V. Kolb-Bachofen, et al. (1991). "Analysis of TNF alpha-induced DNA strand breaks at the single cell level." Am J Pathol 139(2): 251-254.

Ha, Y. M., S. W. Chung, et al. (2010). "Molecular activation of NF-kappaB, pro-inflammatory mediators, and signal pathways in gamma-irradiated mice." Biotechnol Lett 32(3): 373-378.

Hosseinimehr, S. J., R. Nobakht, et al. (2015). "Radioprotective effect of mefenamic acid against radiation-induced genotoxicity in human lymphocytes." Radiat Oncol J 33(3): 256-260.

Jackson, J. H., E. Gajewski, et al. (1989). "Damage to the bases in DNA induced by stimulated human neutrophils." J Clin Invest 84(5): 1644-1649.

Lorimore, S. A., J. A. Chrystal, et al. (2008). "Chromosomal instability in unirradiated hemaopoietic cells induced by macrophages exposed in vivo to ionizing radiation." Cancer Res 68(19): 8122-8126.

Mukherjee, D., P. J. Coates, et al. (2012). "The in vivo expression of radiation-induced chromosomal instability has an inflammatory mechanism." Radiation research 177(1): 18-24.

Nakahira, K., H. P. Kim, et al. (2006). "Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts." J Exp Med 203(10): 2377-2389.

Nakao, N., T. Kurokawa, et al. (2008). "Hydrogen peroxide induces the production of tumor necrosis factor-alpha in RAW 264.7 macrophage cells via activation of p38 and stress-activated protein kinase." Innate Immun 14(3): 190-196.

Narayanan, P. K., K. E. LaRue, et al. (1999). "Alpha particles induce the production of interleukin-8 by human cells." Radiation research 152(1): 57-63.

Natarajan, M., C. F. Gibbons, et al. (2007). "Oxidative stress signalling: a potential mediator of tumour necrosis factor alpha-induced genomic instability in primary vascular endothelial cells." Br J Radiol 80 Spec No 1: S13-22.

Rastogi, S., M. Boylan, et al. (2013). "Interactions of apoptotic cells with macrophages in radiation-induced bystander signaling." Radiation research 179(2): 135-145.

Rastogi, S., P. J. Coates, et al. (2012). "Bystander-type effects mediated by long-lived inflammatory signaling in irradiated bone marrow." Radiation research 177(3): 244-250.

Ratikan, J. A., E. D. Micewicz, et al. (2015). "Radiation takes its Toll." Cancer Lett 368(2): 238-245.

Redon, C. E., J. S. Dickey, et al. (2010). "Tumors induce complex DNA damage in distant proliferative tissues in vivo." Proceedings of the National Academy of Sciences of the United States of America 107(42): 17992-17997.

Saltman, B., D. H. Kraus, et al. (2010). "In vivo and in vitro models of ionizing radiation to the vocal folds." Head Neck 32(5): 572-577.

Shao, C., M. Folkard, et al. (2008). "Role of TGF-beta1 and nitric oxide in the bystander response of irradiated glioma cells." Oncogene 27(4): 434-440.

Shibata, W., S. Takaishi, et al. (2010). "Conditional deletion of IkappaB-kinase-beta accelerates helicobacter-dependent gastric apoptosis, proliferation, and preneoplasia." Gastroenterology 138(3): 1022-1034 e1021-1010.

Stevens, C. R., N. Bucurenci, et al. (1992). "Application of methionine as a detector molecule for the assessment of oxygen radical generation by human neutrophils and endothelial cells." Free Radic Res Commun 17(2): 143-154.

Wang, T. J., C. C. Wu, et al. (2015). "Induction of Non-Targeted Stress Responses in Mammary Tissues by Heavy Ions." PLoS One 10(8): e0136307.

Weigert, A., A. von Knethen, et al. (2018). "Redox-signals and macrophage biology." Mol Aspects Med 63: 70-87.

Yan, B., H. Wang, et al. (2006). "Tumor necrosis factor-alpha is a potent endogenous mutagen that promotes cellular transformation." Cancer Res 66(24): 11565-11570.

Yang, D., S. G. Elner, et al. (2007). "Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells." Exp Eye Res 85(4): 462-472.

Zhang, Q., L. Zhu, et al. (2017). "Ionizing radiation promotes CCL27 secretion from keratinocytes through the cross talk between TNF-alpha and ROS." J Biochem Mol Toxicol 31(3).

Zhao, W. and M. E. Robbins (2009). "Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications." Curr Med Chem 16(2): 130-143.

Zhou, H., V. N. Ivanov, et al. (2005). "Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway." Proceedings of the National Academy of Sciences of the United States of America 102(41): 14641-14646.

Zhou, H., V. N. Ivanov, et al. (2008). "Mitochondrial function and nuclear factor-kappaB-mediated signaling in radiation-induced bystander effects." Cancer Res 68(7): 2233-2240.