To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2003

Relationship: 2003

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

Inhibition, Nuclear factor kappa B (NF-kB) leads to Suppression of T cell activation

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
Impaired IL-1R1 signaling leading to increased susceptibility to infection adjacent High Moderate Cataia Ives (send email) Open for citation & comment EAGMST Under Review

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
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI
Rattus norvegicus Rattus norvegicus High NCBI

Sex Applicability

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

NF-kB plays a crucial role in the activation of dendritic cells as well as T cells. In dendritic cells,  the activation of the canonical NF-kB pathway in response to pro-inflammatory stimuli, such as cytokines including IL-1a or IL-1b and TLR ligands, stimulate the maturation of dendritic cells with enhanced antigen presenting function.  The inhibition of NF-kB suppress antigen presenting function of dendritic cells, resulting in suppression of T cell activation (reviewed by Reinhard et al (Reinhard et al., 2012) and van Delft et al (van Delft, Huitema and Tas, 2015).

In T cells, NF-kB can be activated by several pathways of signal transduction. The engagement of the TCR by major histocompatibility complex (MHC) plus antigen initiates downstream CD3 immunotyrosine activation motif (ITAM) phosphorylation by the Src family kinases, FYN and leukocyte C-terminal src kinase (LCK). Phosphorylated CD3 activates the T cell specific tyrosine kinase, zeta-chain associated protein kinase (ZAP-70), which ultimately trigger calcium release and protein kinase (PK)C activation, respectively. Activation of a specific PKC isoform, PKCμ, connects the above described TCR proximal signaling events to distal events that ultimately lead to NF-kB activation. Importantly, PKCm activation is also driven by engagement of the T cell co-stimulatory receptor CD28 by B7 ligands on antigen presenting cells (APCs). In addition, the stimulation of T cells by IL-1 activates NF-kB as already described before. Once in the nucleus, NF-kB governs the transcription of numerous genes involved in T cell survival, proliferation, and effector functions (Paul and Schaefer, 2013).

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

Mice lacking NF-kB p50 are unable to effectively clear L. monocytogenes and are more susceptible to infection with S. peumoniae (Sha et al., 1995).

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

Although CD4 T cells are able to commit to Th1, Th2 and Th17 lineages in the absence of IL-1R signaling at steady state, these committed CD4 T cells are unable to effectively secrete their cytokines upon TCR ligation. Namely, IL-1 is indispensable for CD4 T cell effector function. (Lin et al, 2015)

RelB deficient mice had an impaired cellular immunity, as observed in contact sensitivity reaction (Weih et al., 1995).

Delayed-type hypersensitivity (DTH) responses were significantly suppressed in IL-1b-deficient and IL-1a/b-deficient mice. Lymph node cells derived from antigen-sensitized IL-1b-deficient and IL-1a/b-deficient mice and IL-1R type I-deficient mice, exhibited reduced proliferative responses against antigen. (Nambu et al., 2006).

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

Interferon-γ (IFN-γ) production in response to CMV-infected fibroblasts was reduced under the influence of MG132 in a dose-dependent manner. A marked reduction was observed at 0.5 μM. Likewise, CMV-specific cytotoxicity of CD8(+) T cells was decreased in the presence of MG132 (Wang et al., 2011).

Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro (Orciuolo et al., 2007).

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

References

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

Fiedler, M.A., Wernke-Dollries, K., Stark, J.M. (1998), Inhibition of TNF-alpha-induced NF-kappaB activation and IL-8 release in A549 cells with the proteasome inhibitor MG-132. Am J Respir Cell Mol Biol 19: 259-268, 10.1165/ajrcmb.19.2.3149

Lin, D., Lei, L., Zhang, Y., et al. (2015), Secreted IL-1alpha promotes T-cell activation and expansion of CD11b(+) Gr1(+) cells in carbon tetrachloride-induced liver injury in mice. Eur J Immunol 45: 2084-2098, 10.1002/eji.201445195

Nambu, A., Nakae, S., Iwakura, Y. (2006), IL-1beta, but not IL-1alpha, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses. Int Immunol 18: 701-712, 10.1093/intimm/dxl007

Nishioka, C., Ikezoe, T., Jing, Y., et al. (2008), DHMEQ, a novel nuclear factor-kappaB inhibitor, induces selective depletion of alloreactive or phytohaemagglutinin-stimulated peripheral blood mononuclear cells, decreases production of T helper type 1 cytokines, and blocks maturation of dendritic cells. Immunology 124: 198-205, 10.1111/j.1365-2567.2007.02755.x

Ohkusu-Tsukada, K., Ito, D., Takahashi, K. (2018), The Role of Proteasome Inhibitor MG132 in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis in NC/Nga Mice. Int Arch Allergy Immunol 176: 91-100, 10.1159/000488155

Orciuolo, E., Galimberti, S., Petrini, M. (2007), Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro. Leuk Res 31: 1026-1027, 10.1016/j.leukres.2006.09.002

Reinhard, K., Huber, M., Lohoff, M., et al. (2012), The role of NF-kappaB activation during protection against Leishmania infection. Int J Med Microbiol 302: 230-235, 10.1016/j.ijmm.2012.07.006

Sha, W.C., Liou, H.C., Tuomanen, E.I., et al. (1995), Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80: 321-330,

van Delft, M.A., Huitema, L.F., Tas, S.W. (2015), The contribution of NF-kappaB signalling to immune regulation and tolerance. Eur J Clin Invest 45: 529-539, 10.1111/eci.12430

Wang, Y., Sun, B., Volk, H.D., et al. (2011), Comparative study of the influence of proteasome inhibitor MG132 and ganciclovir on the cytomegalovirus-specific CD8(+) T-cell immune response. Viral Immunol 24: 455-461, 10.1089/vim.2011.0038

Weih, F., Carrasco, D., Durham, S.K., et al. (1995), Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80: 331-340,

Yu, A., Malek, T.R. (2001), The proteasome regulates receptor-mediated endocytosis of interleukin-2. J Biol Chem 276: 381-385, 10.1074/jbc.M007991200