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Relationship: 2835


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

Increase, Pro-Inflammatory Mediators leads to Increase, Neural Remodeling

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
Deposition of Energy Leading to Learning and Memory Impairment adjacent Moderate Low 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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male Moderate
Female Low
Mixed Moderate
Unspecific Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Moderate
Not Otherwise Specified Low
Juvenile Low

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

Inflammatory mediators such as IL-1β, TNF-α, and IL-6 can affect the normal behavior of neuronal cells through alterations in: (a) the neuronal architecture and (b) synaptic activity. Overexpression of these pro-inflammatory mediators can disrupt the integrity of neurons through increased necrosis and demyelination, decreased neurogenesis, neural stem cell proliferation and synaptic complexity (Cekanaviciute et al., 2018; Fan & Pang, 2017). Structurally, the neuron is comprised of the cell body, dendrites, axon, and axon terminals, all of which are critical in the normal functioning of the central nervous system. Another important component of the neuron is its signaling properties, which uses chemical neurotransmitters to transfer messages in the synaptic cleft (Cekanaviciute et al., 2018; Hladik & Tapio, 2016). Disruption to these structures or signalling properties results in neural remodeling.  

Under physiological conditions, cytokine levels are low, but these can increase in response to various insults. Cytokines mediate immune response through ligand binding to cell surface receptors, which activate signaling cascades such as the JAK-STAT or MAPK pathways to produce or recruit more cytokines. Once organs initiate inflammatory reactions, the cytokines are capable of impairing neuronal function through direct effects on neurons or by indirect mechanisms mediated by microglia, astrocytes or vascular endothelial cells (Mousa & Bakhiet, 2013; Prieto & Cotman, 2018).  

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

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022. Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

Evidence Supporting this KER

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

Overall Weight of Evidence: Moderate

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

Various studies provide support for the biological plausibility of the link between an increase in pro-inflammatory mediators and neural remodeling. It is known that cytokines and their receptors are constitutively expressed by neurons in the central nervous system, and even in normal or pathological states, these cytokines act on neurons (Kishimoto et al., 1994). One important factor in the pathogenesis of neurotoxicity is the overexpression of pro-inflammatory mediators, or Th1-type, cytokines. These cytokines bind to their receptors to induce a conformational change, which triggers the activation of intracellular signaling pathways that alter cell structure and function (Mousa and Bakhiet, 2013). Several sources have reported a change in physical and electrophysiological properties of neurons in either whole-brain samples, specific brain regions such as the hippocampus or dentate gyrus, or neuronal cell cultures in response to increased expression of cytokines (Jenrow et al., 2013; Fan and Pang, 2017; Wong et al., 2004). The main cytokines presenting detrimental effects are IL-1β, TNF-α, and IL-6, which can cause alterations in neuronal architecture such as morphological changes in dendrites and synapses (Tang et al., 2017; Cekanaviciute et al., 2018; Shi et al., 2017). Many studies have also reported decreased proliferation and differentiation in progenitor cells, inhibited neural stem cell differentiation and decreased neurogenesis following increases in cytokines (Zonis et al., 2015; Wong et al., 2004; Tang et al., 2017). IL-6 can affect neurogenesis through various distinct mechanisms. One mechanism is through the stimulation of hypothalamic-pituitary-adrenal axis, which then increases circulating glucocorticoids. These steroids can then inhibit cell proliferation and neurogenesis in the dentate gyrus (Turnbull and Rivier, 1999; Gould et al., 1992; Cameron and Gould, 1994). Decreased neurogenesis in the hippocampus is also well documented as a result of pro-inflammatory mediators, and one possible mechanism for this detrimental effect is through the interaction of IL-1β and orphan nuclear receptor, TLX. This receptor is required to maintain the neural precursor cell pool in neurogenic brain regions, and it has been shown that IL-1β can reduce the expression of TLX and consequently cell proliferation (Ryan et al., 2013). TNF-α affects neuronal fate by interacting with its receptor, TNFR1, which is expressed on neural stem cells. It has been reported that TNFR1-mediated signaling pathway inhibits growth therefore, a reduction in neuron production after TNF-α injection (Chen and Palmer, 2013). A clear mechanistic relationship has not yet been established, although it is accepted that pro-inflammatory mediators can alter the structure and function of neurons.

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
  • Various in vitro studies have reported a stimulation of neural precursor cell proliferation and differentiation or increased neurogenesis by different cytokines such as IL-6 and IFN-γ (Islam et al., 2009; Wong et al., 2004). Another study found increased proliferation within the hippocampus after repeated IL-6 and IL-1β infusion (Seguin et al., 2009). Although a clear mechanism has not yet been elucidated, it is thought that these cytokines have contradictory effects from the differential activation of various signaling cascades (Borsini et al., 2015). For example, hyper-IL-6, a fusion of IL-6 and IL-6 receptor, was found to increase neurogenesis through the activation of MAPK/CREB (mitogen-activated protein kinase/cAMP response element binding protein) cascade (Islam et al., 2009). 

  • Kalm et al. (2013) found a higher inflammatory response in lipopolysaccharide (LPS) treated females compared with males after irradiation. Specifically, increased levels of pro-inflammatory cytokines IL-1β, IL-12, and IL-17, as well as pro-inflammatory chemokines CCL4, CCL3 and CCL2 were detected relative to vehicle-treated animals and LPS-treated males. This was associated with a 32% decrease in DCX+ cells, a marker for neurogenesis, in females. However, in LPS-treated males, a 64% reduction in DCX+ cells compared to vehicle-treated males following irradiation was reported (Kalm et al., 2013). Further research is required to elucidate the exact effects of increased pro-inflammatory mediators on neuronal integrity between males and females. 

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

Modulating Factor 


Effects on the KER 


Drug Therapy 

MW01-2-151SRM (MW-151) – water soluble, nontoxic, bioavailable compound that mitigates pro-inflammatory cytokine production, glial activation and inflammation in rat hippocampus. 

MW-151 reduced the neuroinflammation caused by 10 Gy of heavy ion exposure, thus preserving the integrity of neurogenic signaling in the dentate gyrus. 

Jenrow et al., 2013 

 Genetic Manipulation 

IL-1 receptor antagonist to prevent the interaction between IL-1β with IL-1R1.  

After 7 days in vitro, IL-1β significantly decreased the percentage of DCX-positive neurons, but pre-treatment and subsequent co-treatment with IL-1RA abolished this anti-neurogenic effect of IL-1β. 

Green et al., 2012 


Histamine – an endogenous amine that can regulate both brain inflammation and neurogenesis. 

Histamine treatment significantly increased the total number cells, positively modulates hippocampal neurogenesis, ameliorates the loss of neuronal complexity of hippocampal neuroblasts and reverts synaptic plasticity loss caused by LPS. 

Saraiva et al., 2019 


Tamoxifen – synthetic, non-steroidal estrogen receptor modulator with anti-inflammatory and neuroprotective properties. 

Tamoxifen decreased the production of inflammatory cytokines released from irradiated microglia, attenuating glial activation and decreasing neuronal apoptosis.  

Liu et al., 2010 


Kukoamine A (KuA) – alkaloid extracted from traditional Chinese herb cortex lycii radicis that has been previously reported to have antioxidant properties.  

KuA inhibited radiation-induced increases in pro-inflammatory cytokines, alleviated the activation of hippocampal microglia and ameliorated the suppression of hippocampal neurogenesis. 

Zhang et al., 2017 


Polymorphism that increases the expression of APOE4  increases the risk of developing Alzheimer’s diseases, which generally consists of a decline in memory, thinking and language. 

In homozygous human APOE4 knock-in mice, a dramatic increase in pro-inflammatory cytokines TNF-α, IL-1β and IL-6 was seen after LPS injection compared to the APOE2 and APOE3 alleles, suggesting that APOE4 is implicated in a greater inflammatory response.  

Hunsberger et al., 2019; Zhu et al., 2012 

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


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

Evidence for this relationship comes from rat and mouse models. There is in vivo evidence in both male and female animals, with more evidence in males. Animal age is occasionally not indicated in studies, but most evidence is in adult rodent models. 


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

Borsini, A. et al. (2015), "The role of inflammatory cytokines as key modulators of neurogenesis", Trends in Neurosciences, Vol. 38/3, Elsevier, Amsterdam, 

Cameron, H. A. and E. Gould. (1994), "Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus", Neuroscience, Vol. 61/2, Elsevier, Amsterdam, 

Cekanaviciute, E., S. Rosi and S. V. Costes. (2018), "Central nervous system responses to simulated galactic cosmic rays", International Journal of Molecular Sciences, Vol. 19/11, Multi-Disciplinary Digital Publishing Institute, Basel, 

Chen, Z. and T. D. Palmer. (2013), "Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis", Brain, Behavior, and Immunity, Vol. 30, Elsevier Inc., Amsterdam, 

Dong, X. et al. (2015), "Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of mice", International Journal of Radiation Biology, Vol. 91/3, Taylor & Francis Group, London, 

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, 

Gould, E. et al. (1992), "Adrenal hormones suppress cell division in the adult rat dentate gyrus", The Journal of Neuroscience, Vol. 12/9, Society for Neuroscience, Washington, 

Green, H. F. et al. (2012), "A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells", Molecular and Cellular Neuroscience, Vol. 49/3, Elsevier Inc., Amsterdam, 

Hladik, D. and S. Tapio. (2016), "Effects of ionizing radiation on the mammalian brain", Mutation Research - Reviews in Mutation Research, Vol. 770, Elsevier B.V., Amsterdam, 

Hunsberger, H. C. et al. (2019), "The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions", Neuronal Signaling, Vol. 3/2, Portland Press, London, 

Islam, O. et al. (2009), "Interleukin-6 and Neural Stem Cells: More Than Gliogenesis", (C.-H. Heldin, Ed.)Molecular Biology of the Cell, Vol. 20/1, The American Society for Cell Biology, Rockville, 

Jenrow, K. A. et al. (2013), "Selective Inhibition of Microglia-Mediated Neuroinflammation Mitigates Radiation-Induced Cognitive Impairment", Radiation Research, Vol. 179/5, Bio One, Washington, 

Kalm, M., K. Roughton and K. Blomgren. (2013), "Lipopolysaccharide sensitized male and female juvenile brains to ionizing radiation", Cell Death & Disease, Vol. 4/12, 

Kishimoto, T., T. Taga and S. Akira. (1994), "Cytokine signal transduction", Cell, Vol. 76/2, Elsevier, Amsterdam,

Liu, J.-L. et al. (2010), "Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo", Brain Research, Vol. 1316, Elsevier, Amsterdam, 

Mousa, A. and M. Bakhiet. (2013), "Role of Cytokine Signaling during Nervous System Development", International Journal of Molecular Sciences, Vol. 14/7, Multi-Disciplinary Digital Publishing Institute, Basel, 

Prieto, G. A. and C. W. Cotman. (2017), "Cytokines and cytokine networks target neurons to modulate long-term potentiation", Cytokine & Growth Factor Reviews, Vol. 34, Elsevier, Amsterdam, 

Ryan, S. M. et al. (2013), "Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation", Brain, Behavior, and Immunity, Vol. 33, Elsevier, Amsterdam, 

Saraiva, C. et al. (2019), "Histamine modulates hippocampal inflammation and neurogenesis in adult mice", Scientific Reports, Vol. 9/1, Springer Nature, Berlin, 

Seguin, J. A. et al. (2009), "Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration.", Neuropsychiatric disease and treatment, Vol. 5, Dove Press Ltd., Macclesfield, 

Shi, Q. et al. (2017), "Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice", Science Translational Medicine, Vol. 9/392, American Association for the Advancement of Science, Washington, 

Tang, F. R., W. K. Loke and B. C. Khoo. (2017), "Postnatal irradiation-induced hippocampal neuropathology, cognitive impairment and aging", Brain and Development, Vol. 39/4, Elsevier, Amsterdam, 

Turnbull, A. V. and C. L. Rivier. (1999), "Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action", Physiological Reviews, Vol. 79/1, American Physiology Society, Rockville, 

Valliéres, L. et al. (2002), "Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6", Journal of Neuroscience, Vol. 22/2, Society for Neuroscience, Washington, 

Wong, G., Y. Goldshmit and A. M. Turnley. (2004), "Interferon-γ but not TNFα promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells", Experimental Neurology, Vol. 187/1, Elsevier, Amsterdam, 

Wu, M. D. et al. (2012), "Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running", Brain, Behavior, and Immunity, Vol. 26/2, Elsevier Inc., Amsterdam, 

Zhang, Y. et al. (2017), "Kukoamine A Prevents Radiation-Induced Neuroinflammation and Preserves Hippocampal Neurogenesis in Rats by Inhibiting Activation of NF-κB and AP-1", Neurotoxicity Research, Vol. 31/2, Springer Nature, Berlin, 

Zhu, Y. et al. (2012), "APOE genotype alters glial activation and loss of synaptic markers in mice", Glia, Vol. 60/4, John Wiley & Sons, Inc., Hoboken, 

Zonis, S. et al. (2015), "Chronic intestinal inflammation alters hippocampal neurogenesis", Journal of Neuroinflammation, Vol. 12/1, Springer Nature, Berlin,