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Relationship: 1777

Title

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 Leukocyte recruitment/activation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased pro-inflammatory mediators

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Leukocyte recruitment/activation

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
Endocytic lysosomal uptake leading to liver fibrosis	adjacent	High		Marina Kuburic (send email)	Under development: Not open for comment. Do not cite	Under Review
Increased DNA damage leading to increased risk of breast cancer	adjacent	Moderate	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 Do not cite	Under Development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	Moderate	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 Do not cite	Under Development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

Term	Scientific Term	Evidence	Link
human	Homo sapiens		NCBI
mouse	Mus musculus		NCBI

Sex Applicability

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

Sex	Evidence
Unspecific

Life Stage Applicability

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

Term	Evidence
All life stages

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

Circulating blood leukocytes are required to migrate to sites of injury and infection with the aim to eliminate the primary inflammatory trigger and contribute to tissue repair. In this process are involved selectins (expressed both on leukocytes and endothelium) and integrins (expressed on leukocytes) (von Andrian et al., 1991), with the essential role of the vascular endothelium.

Fast activation of the endothelium with inflammatory stimuli such as histamine and PAF (type I) or slow activation with tumor necrosis factor (TNF) or cytokine interleukin-1 β (IL-1β) (type II), makes the surface of endothelium adhesive (Bevilacqua and Gimbrone, 1987; Pober and Sessa, 2007). This transformation is mediated by a transcriptionally regulated program involving the nuclear factor NF-kB dependent pathway triggered by pro-inflammatory cytokines or bacterial endotoxins (reviewed by Collins et al., 1995).

Integrins mediate attachment between cells or to basement membrane. The β2 integrin family is exclusively expressed on leukocytes and is essential for leukocyte arrest on the endothelium and for migration across the endothelium (Ley et al., 2007). In unstimulated leukocytes integrins are usually in a conformation with low binding affinity, until they receive signals from other receptors, such as chemokine receptors (G-protein-coupled receptors), when they change their conformation and display high affinity for ligands (Luo et al., 2007). Chemokines activate β1 or β2 integrins on monocytes, neutrophils, and lymphocytes and as such serve as chemoattractant for these cells during inflammation (Huber et al., 1991; Tanaka et al., 1993; Gunn et al., 1998).

The chemokines are a family of structurally related cytokines that can act as pro-inflammatory agents (Baggiolini et al., 1994; Vaddi et al., 1997). They have the ability to attract leukocyte subsets to specific sites. They recruit neutrophils, monocytes, natural killer cells (NK) and natural killer T (NKT) cells, all of which express inflammatory chemokine receptors and immature dendritic cells (DCs) that provide the link between innate and adaptive immunity (Oo et al., 2010). After antigen-specific activation of lymphocytes by activated DCs, inflammatory chemokines then attract antigen-specific effector T cells to the inflammatory site (Heydtmann and Adams, 2002).

During diapedesis, leukocytes migrate across the endothelium and basement membrane to enter tissue (Ley et al., 2007; Yadav et al., 2003). Once in tissue, the leukocyte follows chemokine gradients to sites of inflammation, using chemokine-mediated changes in the actin cytoskeleton to propel migration. For example, it was demonstrated that chemokines CXCL9, CXCL10 and CXCL11 are important not only in adhesion, but also in transmigration of effectors T lymphocytes through hepatic endothelium (Curbishley et al., 2005; Eksteen et al., 2004). Intracellular actin reorganization is a prerequisite for cell movement, and it has been shown that chemokines such as SDF-1 induce and increase intracellular filamentous actin in lymphocytes (Bleul et al., 1996).

There is essential role of interleukins, but also other factors such as tumor necrosis factor (TNF), interferon (IFN) in leukocyte recruitment and production of chemokines.

Normally, IL-1β binds to IL-1R1 receptor on the surface of target cells. Following ligand binding the adaptor molecule, myeloid differentiation factor-88 (MyD88), interacts with IL-1R1 via its toll interleukin receptor (TIR) domain (O'Neill, 2008). Signal transduction leads to activation of both mitogen-activated protein kinases (MAPKs) and the transcription factor NF-kB, and resulting in pro-inflammatory cytokine expression. For example, chemokine RANTES production requires the transcription factor NF-kB and the activation of mitogen-activated protein kinases (MAPKs) (Genin et al., 2000; Miyamoto et al., 2000; Kujime et al., 2000, Maruoka et al., 2000; Yang et al., 2000).

TNF-α cleavage produces an intracellular domain that translocates to the nucleus and induces pro-inflammatory cytokine signalling, particularly the expression of IL-12 (Friedman et al., 2006). IL-18 induces natural killer and natural killer T cells to produce IFN-γ (Okamura et al., 1998), but it requires IL-12 to induce IFN-γ production by Th1 cells (Nakanishi et al., 2001). There is an essential role of IFN-I in promoting the chronic recruitment of Ly6Chi monocytes. IFN-I production is elicited via a toll like receptor-7 (TLR-7) and MyD88-dependent pathway (Lee et al., 2008).

While CXC-chemokines, e.g. IL-8, act mostly on neutrophils (Springer, 1995), members of the CC-chemokines, e.g. RANTES and macrophage inflammatory protein have been shown to exert function on monocytes, eosinophils and lymphocytes (Baggiolini et al., 1994; Carr et al., 1994). This depends on the receptors that are expressed on leukocytes. Th1 express preferentially CCR5 and CXCR3, while Th2 cells have CCR3, CCR4 and CCR8 on their surface (Syrbe et al., 1999). Monocytes and macrophages express CCR5 and other receptors for RANTES (Weber et al., 2000).

RANTES chemokine is produced by many cells in the extravascular compartment, including fibroblasts, epithelial cells, and tissue-infiltrating lymphocytes and monocytes (MacEwan, 2002; Hehlgans and Männel, 2002; Black et al., 1997). It acts as a potent chemoattractant for monocytes, memory T cells, eosinophils, and basophils (Schall et al., 1988, 1990; Baggiolini and Dahinden, 1994). Elevated levels of RANTES transcripts are detected within hours of exposure to pro-inflammatory stimuli, including IL-1β, TNF-α, IFN-γ, viruses and LPS (Barnes et al., 1996).

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

There is much evidence that application of chemokines attract leukocytes to specific site in different species (Beck et al., 1997; Lee et al., 2000; Fahy et al., 2001; Nikiforou et al., 2016).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

It was shown that a number of chemokines destabilize the rolling of lymphocytes on L-selectin ligands, suggesting that chemokines are capable of regulating the rolling process (Grabovsky et al., 2002).

Jorgensen and colleagues showed that exposure of mice to FliC^indstrain S. Typhimurium triggered a significant neutrophil influx in the spleen of wild-type mice, but not Il1b⁻/⁻Il18⁻/⁻ mice (Jorgensen et al., 2016).

The expression of chemokines CCL2, CCL7, and CCL12 was reduced dramatically in MyD88-/- mice (Lee et al., 2009).

Miyamoto and colleagues showed that exposure of cells to IL-1β, TNF-α, and IFN-γ resulted in the induction of RANTES mRNA and protein (Ortiz et al., 1996; Miyamoto et al., 2000). The levels of RANTES production by the fibroblasts in the presence of IL-1β or TNF-α were significantly elevated compared with those in the absence of these factors (Yamada et al., 2001).

In the mouse, IFN-γ administration induces high levels of IP-10 expression in liver and kidneys, with lower levels in spleen (Narumi et al., 1992).

CAPE inhibitor of NF-kB blocked partially IL-1β induced expression of chemokines MIP-1a and MIP-1b (Guo et al., 2003).

CCR2 and CCR5 receptors on the CD8 T cells are enriched in the inflamed human liver, and CCR1 is important in the regulation of hepatic inflammation in murine models (Shields et al., 1999; Boisvert et al., 2003).

Intradermal injection of RANTES induces a potent T-lymphocyte and eosinophils recruitment (Fahy et al., 2001; Beck et al., 1997). Intradermal administration of MIP-1a resulted in accumulation of monocytes, lymphocytes, eosinophils and recruitment of neutrophils (Lee et al., 2000).

Direct IL-1α exposure to the gut resulted in increased numbers of CD3+ cells in the fetal sheep ileum when compared with control animals on the first day after the exposure. The number of white blood cells, monocytes, and neutrophils was increased in cord blood after 6 days of IL-1α exposure to the lung and chorioamnion/skin. The number of lymphocytes on the day 6 was increased for the lung. Compared with controls, gut mRNA levels of TNF-α and IL-1 was significantly increased at 6 days after IL-1α exposure to the GI tract (Nikiforou et al., 2016).

IL-1 β induced up-regulation of CXCR4 in certain cancer cells, but in order to do so necessary is that these cells have IL-1R1. Presence of IL-1R antagonist significantly inhibited the up-regulation of CXCR4 induced by IL-1β at both mRNA and protein level (Sun et al., 2015).

SDF-1 is an efficacious chemoattractant and showed a similar dose response for murine lymphocytes and human monocytes, but was not active on human or murine neutrophils. SDF-1 is a highly effective transendothelial chemoattractant (Bleul et al., 1996).

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

Lloyd and colleagues found that several chemokines can stimulate the adherence of peripheral blood lymphocytes to ICAM-1 coated slides (Loyd et al., 1996). However, by using a parallel plate flow chamber, other study failed to observe such an effect (Carr et al., 1996).

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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

Human (Bleul et al., 1996; Miyamoto et al., 2000; Yamada et al., 2001; Sun et al., 2015)

Sheep (Nikiforou et al., 2016)

Mouse (Narumi et al., 1992; Fahy et al., 2001; Lee et al., 2009)

References

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

Baggiolini M, Dahinden CA. CC chemokines in allergic inflammation. Immunol. Today (1994) 15:127–133.

Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemotactic cytokines-CXC and CC chemokines. Adv. Immunol. (1994) 55:97-179.

Barnes DA, Huston M, Holmes R, Benveniste EN, Yong VW, Scholz P, Perez HD. Induction of RANTES expression by astrocytes and astrocytoma cell lines. J. Neuroimmunol. (1996) 71: 207–214.

Beck LA, Dalke S, Leiferman KM, Bickel CA, Hamilton R, Rosen H, Bochner BS, Schleimer RP. Cutaneous injection of RANTES causes eosinophil recruitment: comparison of nonallergic and allergic human subjects. J Immunol. (1997) 159:2962–2972.

Bevilacqua MP, Gimbrone MA Jr. Inducible endothelial functions in inflammation and coagulation. Semin Thromb Hemost. (1987) 13:425–433.

Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner, Johnson RS, Paxton RJ, March CJ, Cerretti DP. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature (1997) 385: 729-733.

Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. (1996) 184(3): 1101–1109.

Boisvert J, Kunkel EJ, Campbell JJ, Keeffe EB, Butcher EC, Greenberg HB. Liver-infiltrating lymphocytes in end-stage hepatitis C virus: subsets, activation status, and chemokine receptor phenotypes. J Hepatol (2003) 38: 67–75.

Carr MW, Alon R, Springer TA. The C-C chemokine MCP-1 differentially modulates the avidity of beta 1 and beta 2 integrins on T lymphocytes. Immunity (1996) 4: 179–187.

Carr MW, Roth S, Luther E, Rose SS, Springer TA. Monocyte chemoattractant protein-1 is a major T lymphocyte chemoattractant. Pro& Natl. Acad. Sci. USA. (1994) 91:3652-3656.

Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J. (1995) 9:899–909.

Curbishley SM, Eksteen B, Gladue RP, Lalor P, Adams DH. CXCR3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow. Am J Pathol (2005) 167: 887–899.

Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hübscher SG, Briskin M, Salmon M, Adams DH. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med (2004) 200: 1511–1517.

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