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Relationship: 994


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

Release, Cytokine leads to Infiltration, Inflammatory cells

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

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

Binding of damage- or pathogen-associated molecular patterns (DAMPs or PAMPs) to pattern recognition receptors (PPRs) such as toll-like receptors (TLRs) can lead to the activation of, amongst others, nuclear factor-κB (NF-κB) or the transcription factor AP-1. This leads to an upregulation of chemokines and inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukins or proteases [1][2]. TLRs are found expressed in most cells, including liver cells such as hepatocytes, Kupffer cells (KCs) or hepatic stellate cells (HPCs) [2]. Upon cytokine secretion, polymorphonuclear neutrophils (PMNs) that, amongst others, circulate in the blood, can become attracted. PMNs are potent phagocytes, but they also lead to pathogen destruction upon oxidative bursting and are for their part capable of pro-inflammatory cytokine production as well. Various endothelial adhesion molecules, such as the intercellular adhesion molecule 1 (ICAM-1), mediate neutrophil adhesion to endothelial cells. ICAM-1 expression on the luminal surface of the capillary is increased during inflammation, and interacts with ß2 integrin, which is expressed on the surface of PMN. Subsequent to adhesion, neutrophils begin to migrate across the endothelium and towards the center of inflammation [3][4]. Interleukin-8 (IL-8) is known to be one of the most potent chemoattractants for the recruitment and activation of neutrophils into various organs (e.g. lung, intestine), and binds to the human CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2) on the surface of the PMN [5][6][7]. But not only IL-8, also macrophage inflammatory protein-2 (MIP-2), growth-regulated oncogenes-α, -β, and -γ, as well as the rodent peptides cytokine-induced neutrophil chemoattractant and KC are all members of the CXC subfamily of chemokines and chemoattractants for inflammatory cells[8]

Cullen and co-workers could further confirm the importance of specific chemokines for chemotaxis of different inflammatory cells. They depleted certain chemokines by using respective antibodies in supernatants of Fas-stimulated HeLa cells (see Relationship:924 for explanation on Fas and its role on cytokine induction) and subsequently assessed the chemotactic activity of immune cells. Only depletion of MCP-1 was sufficient to block almost all THP-1 monocyte chemotaxis. On the other hand, chemotaxis of primary human peripheral blood neutrophils was depending mainly on secreted IL-8. Using an in vivo mouse model, the authors found that Fas stimulation could trigger phagocyte migration by administration of anti-Fas (Jo2) antibody into C57BL/6 mice within 10 h of anti-Fas administration. This correlated with extensive cell death in the thymus and a dramatic increase of CD11b-positive macrophages in the same tissue[9].

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

Secreted chemokines are signalling proteins that attract immune cells to migrate to the infected or damaged tissue, in order to trigger tissue repair, removal of cell bodies or bacteria.

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

Studies exist that report an optimal IL-8 concentration for strongest neutrophil motility, so this KER can actually be quantified. However, this is usually performed ex vivo. Isolated neutrophils are very sensitive towards manual handling and need to be treated with care and within a very short time frame. Therefore, results give an indication on necessary concentrations, but need to be carefully considered with regards to direct transferability to the in vivo situation. Moreover, not only IL-8 is responsible for the recruitment of neutrophils, but also other chemokines can contribute to attraction of inflammatory cells. As they play a minor role, they are usually not considered and included in ex vivo studies.

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

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

[8]: mouse [9][10]: human


List of the literature that was cited for this KER description. More help
  1. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997;388(6640):394-7
  2. 2.0 2.1 Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci. 2016 May;61(5):1294-303
  3. Drost EM, MacNee W. Potential role of IL-8, platelet-activating factor and TNF-alpha in the sequestration of neutrophils in the lung: effects on neutrophil deformability, adhesion receptor expression, and chemotaxis. Eur J Immunol 2002;32(2):393-403
  4. Wang Q, Doerschuk CM, Mizgerd JP. Neutrophils in innate immunity. Semin Respir Crit Care Med 2004;25(1):33-41
  5. Kunkel SL, Standiford T, Kasahara K, Strieter RM. Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung. Exp Lung Res 1991;17(1):17-23
  6. Mitsuyama K, Toyonaga A, Sasaki E, Watanabe K, Tateishi H, Nishiyama T, Saiki T, Ikeda H, Tsuruta O, Tanikawa K. IL-8 as an important chemoattractant for neutrophils in ulcerative colitis and Crohn's disease. Clin Exp Immunol 1994;96(3):432-6
  7. Buanne P, Di Carlo E, Caputi L, Brandolini L, Mosca M, Cattani F, Pellegrini L, Biordi L, Coletti G, Sorrentino C, Fedele G, Colotta F, Melillo G, Bertini R. Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice. J Leukoc Biol 2007;82(5):1239-46
  8. 8.0 8.1 8.2 Faouzi S, Burckhardt BE, Hanson JC, Campe CB, Schrum LW, Rippe RA, Maher JJ. Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway. J Biol Chem. 2001 Dec 28;276(52):49077-82
  9. 9.0 9.1 9.2 Cullen SP, Henry CM, Kearney CJ, Logue SE, Feoktistova M, Tynan GA, Lavelle EC, Leverkus M, Martin SJ. Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells. Mol Cell. 2013 Mar 28;49(6):1034-48
  10. 10.0 10.1 Lin F, Nguyen CM, Wang SJ, Saadi W, Gross SP, Jeon NL. Effective neutrophil chemotaxis is strongly influenced by mean IL-8 concentration. Biochem Biophys Res Commun. 2004 Jun 25;319(2):576-81