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Event: 2097

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, Pro-Inflammatory Mediators

Short name

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
inflammatory response		increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Deposition of Energy Leading to Learning and Memory Impairment	KeyEvent	Vinita Chauhan (send email)	Open for citation & comment

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	Low	NCBI
rat	Rattus norvegicus	Low	NCBI
mouse	Mus musculus	Low	NCBI

Life Stages

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

Life stage	Evidence
Not Otherwise Specified	Moderate

Sex Applicability

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

Term	Evidence
Mixed	Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

(Adapted from KE 1493 - in blue)

Inflammatory mediators are soluble, diffusible molecules that act locally at the site of tissue damage and infection, and at more distant sites. They can be divided into exogenous and endogenous mediators.

Exogenous mediators of inflammation are bacterial products or toxins like endotoxin or lipopolysaccharides (LPS). Endogenous mediators of inflammation are produced from within the (innate and adaptive) immune system itself, as well as other systems. They can be derived from molecules that are normally present in the plasma in an inactive form, such as peptide fragments of some components of complement, coagulation, and kinin systems. Or they can be released at the site of injury by a number of cell types that either contain them as preformed molecules within storage granules, e.g. histamine, or which can rapidly switch on the machinery required to synthesize the mediators.

Pro-inflammatory mediators can have dual properties of anti-inflammatory and pro-inflammatory effects, dysregulation of the balance can lead to chronic inflammation which is implicated in many diseases such as cardiovascular diseases, neurodegenerative diseases or cancer

Examples of pro-inflammatory mediators are provided below in Table 1.

Table 1: a non-exhaustive list of examples for pro-inflammatory mediators

Classes of inflammatory mediators	Examples
Pro-inflammatory cytokines	TNF- α, Interleukins (IL-1, IL-6, IL-8), Interferons (IFN-γ), chemokines (CXCL, CCL, GRO-α, MCP-1), GM-CSF
Prostaglandins	PGE2
Bioactive peptides	Bradykinin
Vasoactive amines	histamine, serotonin
Reactive oxygen species (ROS)	O2-, H2O2
Reactive nitrogen species (RNS)	NO, iNOS

The increased production of pro-inflammatory mediators can have negative consequences on the parenchymal cells leading even to cell death, as described for TNF-a or peroxynitrite on neurons (Brown and Bal-Price, 2003). Along with TNF-α, IL-1β and IL-6 have been shown to exhibit negative consequences on neurogenesis and neuronal precursor cell proliferation when overexpressed. IFN-γ is also associated with neuronal damage, although it is not as extensively studied compared to TNF-α, IL-1β and IL-6. These cytokines are normally involved in brain homeostasis and maintaining tissue repair following an injury, although it can have negative consequences (Fan & Pang, 2017). In addition, via a feedback loop, they can act on the reactive resident cells thus maintaining or exacerbating their reactive state; and by modifying elements of their signalling pathways, they can favour the M1 phenotypic polarization and the chronicity of the inflammatory process (Taetzsch et al., 2015). 

Studies show that the dysregulation of pro-inflammatory mediators can influence both cancer and non-cancer outcomes. Excessive/persistent pro-inflammatory signaling due to injury or exposure to chronic exposures can create an environment conducive to cellular transformation, proliferation. In autoimmune diseases, aberrant immune responses driven by pro-inflammatory cytokines like IL-6 and TNF-α lead to chronic inflammation, tissue damage, and organ dysfunction. Neurodegenerative disorders, such as Alzheimer's disease, involve dysregulated pro-inflammatory mediators like IL-1β and TNF-α, contributing to neuronal degeneration. Basically, this event occurs equally in various tissues and does not require tissue-specific descriptions. Nevertheless, there are some specificities such as the release of glutamate by brain reactive glial cells (Brown and Bal-Price, 2003; Vesce et al., 2007). The differences may rather reside in the type of insult favouring the increased expression and/or release of a specific class of inflammatory mediators, as well the time after the insult reflecting different stages of the inflammatory process. For these reasons, the analyses of the changes of a battery of inflammatory mediators rather than of a single one is a more adequate measurement of this KE.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed.

Assay	Reference	Description	OECD Approved Assay
RT-qPCR Q-PCR	(Veremeyko et al., 2012; Alwine et al, 1977; Forlenza et al., 2012)	Measures mRNA expression of cytokines, chemokines and inflammatory markers	No
Immunoblotting (western blotting)	(Lee et al., 2008)	Uses antibodies specific to proteins of interest, can used to detect presence of pro-inflammatory mediators in samples of cell or tissue lysate	No
Whole blood stimulation assay	(Thurm & Halsey, 2005)	Detects inflammatory cytokines in blood	No
Imaging tests	(Rollins & Miskolci, 2014)	A qualitative technique using a cytokine specific antibodies and fluorophores can be used to visualize expression patterns, subcellular location of the target and protein-protein interactions. Common examples include double immunofluorescence confocal microscopy or other molecular imaging modalities.	No
Flow-cytometry	(Karanikas et al., 2000)	Detects the intracellular cytokines with stimulation.	No
Immunoassays (ex. enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunospot (ELISpot), radioimmunoassay)	(Amsen et al., 2009; Engvall & Perlmann, 1972; Ji & Forsthuber, 2016; Goldsmith, 1975)	Plate based assay technique using antibodies to detect presence of a protein in a liquid sample. Can be used to identify presence of an inflammatory cytokine of interest especially when in low concentrations.	No
Inflammatory cytokine arrays	(Amsen et al., 2009)	Similar to the ELISA, except using a membrane-based rather than plate-based approach. Can be used to measure multiple cytokine targets concurrently.	No
Immunohistochemistry (IHC)	(Amsen et al., 2009; Coons et al., 1942)	Immobilized tissue or cell cultures are stained using antibodies for specificity of ligands of interest. Versions of the assays can be used to visualize localization of inflammatory cytokines.	No

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic applicability: The inflammatory response and increase of the pro-inflammatory mediators has been observed across species from simple invertebrates such as Daphnia to higher order vertebrates (Weavers & Martin, 2020).

Life stage applicability: This key event is not life stage specific (Kalm et al., 2013; Veeraraghan et al., 2011; Hladik & Tapio, 2016).

Sex applicability: Most studies conducted were on male models, although sex-dependent differences in pro-inflammatory markers have been previously reported (Cekanaviciute et al., 2018; Parihar et al., 2020).

Evidence for perturbation by a prototypic stressor: There is evidence of the increase of pro-inflammatory mediators following perturbation from a variety of stressors including exposure to ionizing radiation. (Abdel-Magied et al., 2019; Cho et al., 2017; Gaber et al., 2003; Ismail et al., 2016; Kim et al. 2002; Lee et al., 2010; Parihar et al., 2018)

References

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

Abdel-Magied, N., S. M., Shedid and Ahmed, A. G. (2019), “Mitigating effect of biotin against irradiation-induced cerebral cortical and hippocampal damage in the rat brain tissue”, Environmental Science and Pollution Research, Vol. 26/13, Springer, London, https://doi.org/10.1007/S11356-019-04806-X.

Alwine, J. C., D. J. Kemp and G. R. Stark (1977), “Method for detection of specific RNAs in agarose gels by transfer to diazobenzyloxymethyl-paper and hybridization with DNA probes”, Proceedings of the National Academy of Sciences of the United States of America, Vol. 74/12, United States National Academy of Sciences, Washington, D.C., https://doi.org/10.1073/pnas.74.12.5350

Amsen, D., de Visser, K. E., and Town, T. (2009), “Approaches to determine expression of inflammatory cytokines”, in Inflammation and Cancer, Humana Press, Totowa, https://doi.org/10.1007/978-1-59745-447-6_5

Brown, G. C., and A. Bal-Price (2003), “Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria”, Molecular Neurobiology, Vol. 27/3, Springer, London, https://doi.org/10.1385/MN:27:3:325

Cekanaviciute, E., S. Rosi and S. Costes. (2018), "Central Nervous System Responses to Simulated Galactic Cosmic Rays", International Journal of Molecular Sciences, Vol. 19/11, Multidisciplinary Digital Publishing Institute (MDPI) AG, Basel,  https://doi.org/10.3390/ijms19113669. 

Cho, H. J. et al. (2017), “Role of NADPH Oxidase in Radiation-induced Pro-oxidative and Pro-inflammatory Pathways in Mouse Brain”, International Journal of Radiation Biology, Vol. 93/11, Informa, London, https://doi.org/10.1080/09553002.2017.1377360.

Coons, A. H. et al. (1942), “The Demonstration of Pneumococcal Antigen in Tissues by the Use of Fluorescent Antibody”, The Journal of Immunology, Vol. 45/3, American Association of Immunologists, Minneapolis, pp. 159-169

Engvall, E., and P. Perlmann (1972), “Enzyme-Linked Immunosorbent Assay, Elisa”, The Journal of Immunology, Vol. 109/1, American Association of Immunologists, Minneapolis, pp. 129-135

Fan, L. W. and Y. Pang. (2017), "Dysregulation of neurogenesis by neuroinflammation: Key differences in neurodevelopmental and neurological disorders", Neural Regeneration Research, Vol. 12/3, Wolters Kluwer, Alphen aan den Rijn, https://doi.org/10.4103/1673-5374.202926. 

Forlenza, M. et al. (2012), “The use of real-time quantitative PCR for the analysis of cytokine mRNA levels” in Cytokine Protocols, Springer, New York, https://doi.org/10.1007/978-1-61779-439-1_2 

Gaber, M. W. et al. (2003), “Differences in ICAM-1 and TNF-alpha expression between large single fraction and fractionated irradiation in mouse brain”, International Journal of Radiation Biology, Vol. 79/5, Informa, London, https://doi.org/10.1080/0955300031000114738.

Goldsmith, S. J. (1975), "Radioimmunoassay: Review of basic principles", Seminars in Nuclear Medicine, Vol. 5/2, https://doi.org/10.1016/S0001-2998(75)80028-6.

Hladik, D. and S. Tapio. (2016), "Effects of ionizing radiation on the mammalian brain", Mutation Research/Reviews in Mutation Research, Vol. 770, Elsevier B. b., Amsterdam, https://doi.org/10.1016/j.mrrev.2016.08.003. 

Ismail, A. F. M., A.A.M. Salem and M.M.T. Eassawy (2016), “Modulation of gamma-irradiation and carbon tetrachloride induced oxidative stress in the brain of female rats by flaxseed oil”, Journal of Photochemistry and Photobiology B: Biology, Vol. 161, Elsevier, Amsterdam, https://doi.org/10.1016/J.JPHOTOBIOL.2016.04.031.

Ji, N. and T. G. Forsthuber. (2014), "ELISPOT Techniques" (pp. 63–71), https://doi.org/10.1007/7651_2014_111.

Kalm, M., K. Roughton and K. Blomgren. (2013), "Lipopolysaccharide sensitized male and female juvenile brains to ionizing radiation", Cell Death & Disease, Vol. 4/12, Nature Publishing Group, Berlin, https://doi.org/10.1038/cddis.2013.482.

Karanikas, V. et al. (2000), “Flow cytometric measurement of intracellular cytokines detects immune responses in MUC1 immunotherapy”, Clinical Cancer Research, Vol. 6/3, American Association for Cancer Research, Philadelphia, pp. 829–837

Kim, S. H. et al. (2002), “Expression of TNF-alpha and TGF-beta 1 in the rat brain after a single high-dose irradiation”, Journal of Korean Medical Science, Vol. 17/2, Korean Medical Association, Seoul, https://doi.org/10.3346/JKMS.2002.17.2.242.

Lee, J. W. et al. (2008), “Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation”, Journal of Neuroinflammation, Vol. 5/1, BioMed Central, London, https://doi.org/10.1186/1742-2094-5-37

Lee, W. H. et al. (2010), “Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain”, International Journal of Radiation Biology, Vol. 86/2, Informa, London, https://doi.org/10.3109/09553000903419346.

Parihar, V. K. et al. (2018), “Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice”, Experimental Neurology, Vol. 305, Elsevier, Amsterdam, https://doi.org/10.1016/J.EXPNEUROL.2018.03.009.

Parihar, V. K. et al. (2020), "Sex-Specific Cognitive Deficits Following Space Radiation Exposure", Frontiers in Behavioral Neuroscience, Vol. 14, https://doi.org/10.3389/fnbeh.2020.535885.

Rollins, J. and V. Miskolci (2014), “Immunofluorescence and subsequent confocal microscopy of intracellular TNF in human neutrophils” in Cytokines Bioassays, Springer, London, https://doi.org/10.1007/978-1-4939-0928-5_24

Taetzsch, T. et al. (2015), "Redox regulation of NF-κB p50 and M1 polarization in microglia", Glia, Vol. 63/3, John Wiley & Sons, Hoboken, https://doi.org/10.1002/glia.22762.

Thurm, C. W. and J. F. Halsey (2005), “Measurement of Cytokine Production Using Whole Blood”, in Current Protocols in Immunology, John Wiley & Sons, Inc., Hoboken, https://doi.org/10.1002/0471142735.im0718bs66

Veeraraghavan, J. et al. (2011), "Low-dose γ-radiation-induced oxidative stress response in mouse brain and gut: Regulation by NFκB–MnSOD cross-signaling", Mutation Research/Genetic Toxicology and Environmental Mutagenesis, Vol. 718/1–2, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrgentox.2010.10.006.

Veremeyko, T. et al. (2012), “Detection of microRNAs in microglia by real-time PCR in normal CNS and during neuroinflammation”, Journal of Visualized Experiments: JoVE, Vol. 65, MyJove Corporation, Cambridge, https://doi.org/10.3791/4097

Vesce, S. et al. (2007), “Glutamate release from astrocytes in physiological conditions and in neurodegenerative disorders characterized by neuroinflammation”, International Review of Neurobiology, Vol. 82, Elsevier, Amsterdam, https://doi.org/10.1016/S0074-7742(07)82003-4

Weavers, H. and P. Martin (2020), “The cell biology of inflammation: From common traits to remarkable immunological adaptations”, Journal of Cell Biology, Vol. 219, Rockefeller University Press, New York, https://doi.org/10.1083/jcb.202004003