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Relationship: 2053


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 proinflammatory mediators leads to Increased transcription of genes encoding acute phase proteins

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
Substance interaction with lung resident cell membrane components leading to atherosclerosis adjacent High Moderate Arthur Author (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 Do not cite Under Development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
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
human Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

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

This KER presents the association between the secretion of pro-inflammatory mediators (Key event 1496) and transcription of genes enconding acute phase proteins (Key event 1438) in different tissues, mainly lungs and liver. The evidence of the KER presented is based on in vitro studies, animal studies (mice) and human studies.

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
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

The biological plausibility is high. It is known that acute phase proteins are induced by pro-inflammatory cytokines, primary interleukin (IL)-6, IL-1β, and tumor necrosis factor α (TNF-α). These cytokines are produced at sites of inflammation, mainly by monocytes and macrophages (Gabay & Kushner, 1999; Mantovani & Garlanda, 2023; Uhlar & Whitehead, 1999; Venteclef, Jakobsson, Steffensen, & Treuter, 2011). Following cytokine release, signaling cascades and transcription factors are activated, regulating the expression of acute phase reaction genes (Venteclef et al., 2011).

In this KER, pulmonary inflammation has been considered as an indirect marker of the release of pro-inflammatory factors because the release of inflammatory mediators (i.e. cytokines and chemokines) recruits immune cells to inflammation sites (Janeway, Murphy, Travers, & Walport, 2008). In mice, pulmonary inflammation is commonly assessed as the number or fraction of neutrophils in the broncheoalveolar lavage fluid (BALF) (Van Hoecke, Job, Saelens, & Roose, 2017).

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

The table in the following link presents inconsistencies for this KER, where secretion of pro-inflammatory mediators has been observed after exposure to a stressor, while systemic acute phase response was not observed, or viceversa. Secretion of pro-inflammatory mediators was measured as change in concentration of pro-inflammatory markers in blood or increase neutrophil numbers in bronchoalveolar lavage fluid (BALF), while the transcription of genes encoding acute phase proteins was measured in tissues: Inconsistent evidence KER2.

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

Neutrophil number in brochoalveolar lavage fluid (indirect measure of the secretion of proinflammatory mediators (Key event 1496) correlates with the expression of Saa3 mRNA levels in lung tissue (Key event 1438), in female C57BL/6J mice 1 and 28 days after intratracheal instillation of metal oxide nanomaterials (Figure 1). The Pearson’s correlation coefficient was 0.82 (p<0.001) between log-transformed neutrophil numbers in brochoalveolar lavage fluid and log-transformed Saa3 mRNA levels in lung tissue (Gutierrez et al., 2023).

Figure 1. Correlations between neutrophil numbers and Saa3 mRNA levels in lung tissue, including data from 1 and 28 days after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).

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

It has been shown that pro-inflammatory mediators concentrations increase before the expression of genes enconding acute phase proteins:

  • Upregulation of cytokine genes [Interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α] was shown to peak around 2h after pulmonary exposure to lipopolysaccharide in female C57BL/6J mice, while upregulation serum amyloid A genes showed their highest upregulation at 8-12h after exposure (Jeyaseelan et al., 2004).
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

Some acute phase proteins (f. ex. C-reactive protein, serum amyloid A and complement components) have pro-inflammatory functions, including induction of inflammatory cytokines, chemotaxis and activation of immune cells. On the other hand, other acute phase proteins present anti-inflammatory functions (f. ex. Haptoglobin and fibrinogen) as antioxidative and tissue repair inducer (Gabay & Kushner, 1999).

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

Acute phase response is present in vertebrate species (Cray, Zaias, & Altman, 2009). In addition, serum amyloid A, one of the major acute phase proteins, has been conserved in mammals throughout evolution and has been described in humans, mice, dogs, horses, among others (Uhlar & Whitehead, 1999).


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

Cray, C., Zaias, J., & Altman, N. H. (2009). Acute phase response in animals: a review. Comp Med, 59(6), 517-526.

Gabay, C., & Kushner, I. (1999). Acute-phase proteins and other systemic responses to inflammation. N Engl J Med, 340(6), 448-454. doi:10.1056/NEJM199902113400607

Gutierrez, C. T., Loizides, C., Hafez, I., Brostrom, A., Wolff, H., Szarek, J., . . . Vogel, U. (2023). Acute phase response following pulmonary exposure to soluble and insoluble metal oxide nanomaterials in mice. Part Fibre Toxicol, 20(1), 4. doi:10.1186/s12989-023-00514-0

Husain, M., Saber, A. T., Guo, C., Jacobsen, N. R., Jensen, K. A., Yauk, C. L., . . . Halappanavar, S. (2013). Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation. Toxicol Appl Pharmacol, 269(3), 250-262. doi:10.1016/j.taap.2013.03.018

Jackson, P., Hougaard, K. S., Vogel, U., Wu, D., Casavant, L., Williams, A., . . . Halappanavar, S. (2012). Exposure of pregnant mice to carbon black by intratracheal instillation: toxicogenomic effects in dams and offspring. Mutat Res, 745(1-2), 73-83. doi:10.1016/j.mrgentox.2011.09.018

Janeway, C., Murphy, K. P., Travers, P., & Walport, M. (2008). Janeway's immunobiology (7. ed. / Kenneth Murphy, Paul Travers, Mark Walport. ed.). New York, NY: Garland Science.

Jeyaseelan, S., Chu, H. W., Young, S. K., & Worthen, G. S. (2004). Transcriptional profiling of lipopolysaccharide-induced acute lung injury. Infect Immun, 72(12), 7247-7256. doi:10.1128/IAI.72.12.7247-7256.2004

Kopf, M., Baumann, H., Freer, G., Freudenberg, M., Lamers, M., Kishimoto, T., . . . Kohler, G. (1994). Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature, 368(6469), 339-342. doi:10.1038/368339a0

Mantovani, A., & Garlanda, C. (2023). Humoral Innate Immunity and Acute-Phase Proteins. N Engl J Med, 388(5), 439-452. doi:10.1056/NEJMra2206346

Meek, R. L., Urieli-Shoval, S., & Benditt, E. P. (1994). Expression of apolipoprotein serum amyloid A mRNA in human atherosclerotic lesions and cultured vascular cells: implications for serum amyloid A function. Proc Natl Acad Sci U S A, 91(8), 3186-3190. doi:10.1073/pnas.91.8.3186

Ramadori, G., Van Damme, J., Rieder, H., & Meyer zum Buschenfelde, K. H. (1988). Interleukin 6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse. Comparison with interleukin 1 beta and tumor necrosis factor-alpha. Eur J Immunol, 18(8), 1259-1264. doi:10.1002/eji.1830180817

Uhlar, C. M., & Whitehead, A. S. (1999). Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem, 265(2), 501-523. doi:10.1046/j.1432-1327.1999.00657.x

Van Hoecke, L., Job, E. R., Saelens, X., & Roose, K. (2017). Bronchoalveolar Lavage of Murine Lungs to Analyze Inflammatory Cell Infiltration. J Vis Exp(123). doi:10.3791/55398

Venteclef, N., Jakobsson, T., Steffensen, K. R., & Treuter, E. (2011). Metabolic nuclear receptor signaling and the inflammatory acute phase response. Trends Endocrinol Metab, 22(8), 333-343. doi:10.1016/j.tem.2011.04.004