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Relationship: 2018

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

Increase of IL-23 leads to Th17 cell migration and inflammation induction

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
Stimulation of TLR7/8 in dendric cells leading to Psoriatic skin disease adjacent High High Evgeniia Kazymova (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 Do not cite Under Development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

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

IL-23 is important for differentiation and proliferation of Th17 cells. As a major source of IL-23, Tip-DC is present in the skin lesions of psoriatic patients and works to activate the Th17 pathway (Hansel et al. 2011).

Signaling through the heterodimeric IL-23 receptor (subunits of p19 and p40) of Th17 cells stimulates the production of proinflammatory keratinocyte cytokines that mediate the psoriatic response and induces the production of IL-17. Th17 cells are increased in the peripheral blood and lesion skin of psoriatic patients, and IL-17 and IL-22 produced from Th17 act on epidermal keratinocytes to cause inflammatory chemokines and hyperproliferation (Michelle A. et al. 2005).

IL-17A, which is highly expressed by Th17 cells, has a direct effect on the regulation of genes expressed by keratinocytes that are involved in innate immune defense, including defensins,8, 9 S100 family proteins, lipocalin, and LL37/cathelicidin, as well as a range of CXCL chemokines that regulate neutrophil trafficking (Gilliet et al. 2004). IL-22, which is expressed by Th22 and Th17 cells, and related IL-20 family members promote keratinocyte hyperproliferation and abnormal differentiation (Krueger et al. 2012).

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

IL-17A, which is highly expressed by TH17 cells, has a direct effect on the regulation of genes expressed by keratinocytes that are involved in innate immune defense, thorough expressions of defensins,8, 9, S100 family proteins, lipocalin and LL37/cathelicidin, as well as a range of CXCL chemokines that regulate neutrophil trafficking. IL-22, which is expressed by TH22 and TH17 cells, and related IL-20 family members promote keratinocyte hyperproliferation and abnormal differentiation (Gilliet et al.2012).

In vitro Reconstituted Human Epidermis (RHE) model stimulated for 48 hours with medium containing IL-17, IL-22 and TNFα mix (concentration 3 ng / mL) as psoriasis-specific cytokines. Controls were cultured in normal medium. After fixing RHE and embedding in paraffin, 4 μm sections were stained with hematoxylin-eosin or immunolabeled with anti-filaggrin, anti-S100A7, anti-hBD-2 mAb.

RHE stimulated with cytokine mix showed dramatic expression of these protein. In the RHE with normal medium, antibacterial peptide S100A7 was expressed locally, but BD-2 protein was not detected. This is due to the synergistic effect of IL-17 added to the IL-22 / TNFα combination. Filaggrin, S100A7 and BD-2 mRNA expression by RT-qPCR analysis increased 20-fold (S100A7) or -50-fold (BD-2) compared to controls. This is a downstream event that can be modeled using keratinocytes and cytokines and relies on upstream mechanisms of recruitment and activation of other innate adaptive immune cells.(Bernard et al. 2012.).

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

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

KE1:

IL-23, which maintains Th17 cells, is released from TNF-a and inducible nitric oxide synthase (iNOS) -producing dendritic cells (TIP-DC). TIP-DC activates IL-17, IL-22, IL-23, and TNF-a mRNA expression in psoriatic skin. Cytokine staining analysis of peripheral blood mononuclear cell (PBMC) in patients with psoriasis showed a three-fold increase in Th17 cells compared to normal PBMC. Thl7 cells produce IL-22 and stimulate keratinocyte proliferation. IL-22 activates STAT3 and induces the production of cytokine (such as IL-8), chemokines and the synthesis of antimicrobial peptides (Zaba et al. 2005).

KE 2

The epidermis of psoriasis patients did not have many T cells, but the analysis was similar to peripheral blood and dermis. The proportion of Th17 cells in the dermis was significantly higher than that in normal skin, and TNF and IFN-g were produced from Th17 cells. Skin and peripheral blood contained a subset of Th17 cells producing IFN-g / TNF.

Keratin 16, IL-17, IFN-g, and IL-22 mRNA expression increased in psoriatic skin, but cyclosporine therapy returned these mRNA to normal levels. The average expression of IL-17 / human acidic ribosomal protein (hARP) in non-lesional skin was 0.4 compared to 10.8 in lesional skin, and cyclosporine administration returned to non-lesional levels. That IL-17 mRNA return to baseline, effective treatment supports that Th17 in psoriasis is a central pathogenic.(Lowes et al.2008)

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

In mice, application of IL-23 causes psoriatic-like epidermal hyperplasia, but this effect does not occur in IL-17A and IL-22KO mice. Therefore, it is thought that IL-17A and IL-22 play an important role downstream of IL-23(Rizzo HL. Et al. 2011).

Recombinant mIL-23 (rmIL-23) injected into the ear of WT mice induced IL-17A and IL-22 expression, and showed ear swelling and epidermal hyperplasia. When rmIL-23 was injected into IL-22 KO mice, IL-22 was induced, but ear swelling and epidermal hyperplasia were less than in WT mice. When rmIL-23 was injected into IL-17A KO mice, IL-22 was induced, but ear swelling and epidermal hyperplasia hardly occurred. WT mice after administration of IL-22 or IL-17A inhibitor completely inhibited IL-23-induced epidermal hyperplasia. These results indicate that two cytokines, IL-22 and IL-17A, are downstream mediators of IL-23-induced changes in mouse skin and are required for the generation of IL-23-mediated skin lesions. (Hansel et al. 2011)

References

List of the literature that was cited for this KER description. More help
  1. Anja Hänsel,Claudia Günther, Jens Ingwersen, Josephine Starke, Marc Schmitz, MichaelBachmann,Michael Meurer, Ernst Peter Rieber, Knut Schäkel. Human slan (6-sulfo LacNAc) dendritic cells are inflammatory dermal dendritic cells in psoriasis and drive strong TH17/TH1 T-cell responses.J.Allergy. Clin. Immunol. 2011, 127, 787-794.
  2. Michelle A. Lowes, Francesca Chamian, Maria Veronica Abello, Judilyn Fuentes-Duculan,Shao-Lee Lin, Rachel Nussbaum, Inna Novitskaya, Henrietta Carbonaro, Irma Cardinale, Toyoko Kikuchi, Patricia Gilleaudeau, Mary Sullivan-Whalen, Knut M. Wittkowski, Kim Papp, Marvin Garovoy, Wolfgang Dummer, Ralph M. Steinman, James G. Kruege. Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a). Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 19057–19062.
  3. James G Krueger, Scott Fretzin, Mayte Suarez-Farinas, Patrick A Haslett, Krista M Phipps, Gregory S Cameron, Juliet Mccolm, Artemis Katcherian, Inna Cueto, Traci White, Subhashis Banerjee, and Robert W Hoffman. IL-17A is essential for cell activation and inflammatory gene ciorcuits in subjects with psoriasis. Jourmal of Allergy and Clinical Immunology 2012, 130(1): 145-154
  4. Michel Gilliet, Curdin Conrad, Michael Geiges, Antonio Cozzio, Wolfgang Thürlimann, Günter Burg, Frank O. Nestle, Reinhard Dummer. Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors.Arch.Dermatol.2004, 140, 1490-1495.・Bernard 2012
  5. Lisa C. Zaba, Irma Cardinale, Patricia Gilleaudeau, Mary Sullivan-Whalen, Mayte Suárez-Fariñas, Judilyn Fuentes-Duculan, Inna Novitskaya, Artemis Khatcherian, Mark J. Bluth, Michelle A. Lowes, James G. Krueger. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J. Exp. Med. 2007, 204, 3183-3194.
  6. Michelle A. Lowes, Toyoko Kikuchi, Judilyn Fuentes-Duculan, Irma Cardinale, Lisa C. Zaba, Asifa S. Haider, Edward P. Bowman, and James G. Krueger. Psoriasis Vulgaris Lesions Contain Discrete Populations of Th1 and Th17 T Cells. Journal of Investigative Dermatology. 2008, 128, 1207-1211.
  7. Rizzo HL, Kagami S, Phillips KG, Kurtz SE, Jacques SL, Blauvelt A. IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. J Immunol. 2011 Feb 1; 186(3): 1495-502.