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Event: 87

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Release, Cytokine

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Release, Cytokine
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
eukaryotic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
cytokine secretion Cytokine increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11) KeyEvent Mathieu Vinken (send email) Under development: Not open for comment. Do not cite Under Development
Frustrated phagocytosis-induced lung cancer KeyEvent Carole Seidel (send email) Under development: Not open for comment. Do not cite Under Development
TLR9 activation leading to Multi Organ Failure and ARDS KeyEvent Gillina Bezemer (send email) Under development: Not open for comment. Do not cite
Endothelial cell dysfunction leading to thromboinflammation KeyEvent Luigi Margiotta-Casaluci (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI

Life Stages

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

Sex Applicability

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

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Cytokines are small, soluble molecules secreted by cells to enable intercellular communication. Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), as well as on distant cells (endocrine action). Cytokines can act synergistically or antagonistically, and secretion from one cell can trigger upregulation of a further range of cytokines from the same cell or others [1]. Most cells in the body are able to secrete them, and several subfamilies belong to the group of cytokines, such as chemokines, interferons, interleukins, tumor necrosis factors (TNF), transforming growth factors (TGF) and colony-stimulating factors. They are important players in modulating fundamental biological processes, including body growth, adiposity, lactation, hematopoiesis, and also inflammation and immunity[2]. Damaged cells, such as apoptotic cells, can trigger the upregulation and release of cytokines to induce the inflammatory response. An important receptor responsible for cell death-related cytokine regulation is Fas, a cell surface glycoprotein which belongs to the tumor necrosis factor (TNF) receptor family. The role of Fas in the onset of inflammation by upregulating inflammatory cytokines is increasingly discussed. Fas-activation can trigger the production of MCP-1 and IL-8 and its associated chemotaxis of phagocytes toward apoptotic cells[3].

TNF-α is an inflammatory mediator that can be secreted by many cell types, including hepatocytes and Kupffer cells. TNF-induced cytokines and chemokines, such as IL-6, IL-8, GMCSF, CXCL1, and RANTES, can trigger immune responses by producing acute phase proteins and recruitment of inflammatory cells such as neutrophils, macrophages, and basophils to the site of inflammation. Moreover, an increased production of monocytes/macrophages from bone marrow is triggered[3].

On the other hand, inflammation can be suppressed by cytokines and mediators such as IL-10 and TGF-β. In the liver, TGF-β1 is the most abundant isoform and is secreted by immune cells, stellate cells, and epithelial cells. IL-10 inhibits T cell-, monocyte-, and macrophage-mediated functions and has been detected in several liver cells, in¬cluding hepatocytes, stellate cells, and Kupffer cells [2].

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

mRNA expression levels of inflammatory cytokines can be determined by using real-time PCR as described in [4]. Equally, In Situ Hybridization of mRNA in liver tissue can be used [5].

Plasma levels of pro-inflammatory cytokines, or levels in cell supernatants can be analysed by enzyme linked immunosorbent assay (ELISA) using commercial kits [6][3]. A more advanced system was described recently by using a multiplex immunoassay platform. In a 96 well plate format the authors describe the analysis of blood, urine and breath samples of human volunteers in a Meso Scale Discovery (MSD) multiplex electrochemiluminescent immunoassay system [7].

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

[4][6][5]: mouse [3][7]: human

References

List of the literature that was cited for this KE description. More help
  1. Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007 Spring;45(2):27-37
  2. 2.0 2.1 Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol. 2012 Feb 28;18(8):727-35
  3. 3.0 3.1 3.2 3.3 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
  4. 4.0 4.1 Cui Y, Liu H, Zhou M, Duan Y, Li N, Gong X, Hu R, Hong M, Hong F. Signaling pathway of inflammatory responses in the mouse liver caused by TiO2 nanoparticles. 2011; J. Biomed. Mater. Res. - Part A 96 A:221–229
  5. 5.0 5.1 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
  6. 6.0 6.1 Ma L, Zhao J, Wang J, Liu J, Duan Y, Liu H, Li N, Yan J, Ruan J, Wang H, Hong F. The Acute Liver Injury in Mice Caused by Nano-Anatase TiO2. Nanoscale Res Lett. 2009 Aug 1;4(11):1275-85
  7. 7.0 7.1 Stiegel MA, Pleil JD, Sobus JR, Morgan MK, Madden MC. Analysis of inflammatory cytokines in human blood, breath condensate, and urine using a multiplex immunoassay platform. Biomarkers. 2015 Feb;20(1):35-46