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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

Inhibition, Nuclear factor kappa B (NF-kB)

Downstream event

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

Suppression of T cell 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
Impaired IL-1R1 signaling leading to Impaired T-Cell Dependent Antibody Response	adjacent	High	Moderate	Cataia Ives (send email)	Open for citation & comment	WPHA/WNT Endorsed

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. Antigen-specific CD4+ T cell proliferative responses were significantly reduced following co-culture with IL-1RI−/− dendritic cells (DCs) (Nambu et al., 2006).

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

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

Quite a few NF-kB inhibitors have been reported. MG132, bortezomib, curcumin, DHMEQ(Dehydroxymethylepoxyquinomicin), naringin, sorafenib, genistein and parthenolide are some of representatives (Pordanjani and Hosseinimehr, 2016).

Interferon-γ (IFN-γ) production in response to CMV-infected fibroblasts was reduced under the influence of MG132, a proteosome inhibitor as well as a NF-kB inhibitor, 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).

In vivo MG132 administration to NC/Nga mice with DNFB-induced dermatitis reduced Th17 cells but maintained the level of Th1 cells, resulting in the alleviation of dermatitis lesions by decreasing both serum IgE hyperproduction and mast cell migration (Ohkusu-Tsukada et al., 2018).

Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro (Satou et al., 2004). Bortezomib inhibits T-cell function versus infective antigenic stimuli in a dose-dependent manner in vitro (Orciuolo et al., 2007).

Dehydroxymethylepoxyquinomicin (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 (Nishioka et al., 2008).

Regarding the suppression of NF-kB by impaired IL-1 signaling, it was reported that delayed-type hypersensitivity (DTH) responses were significantly suppressed in IL-1β-deficient and IL-1α/β-deficient mice. Lymph node cells derived from antigen-sensitized IL-1β-deficient and IL-1α/β-deficient mice and IL-1R type I-deficient mice, exhibited reduced proliferative responses against antigen. These data suggest that IL-1β is necessary for the efficient priming of T cells. In addition, CD4+ T cell-derived IL-1 plays an important role in the activation of DCs during the elicitation phase, resulting in the production of TNF, that activate allergen-specific T cells (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

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

A representative NF-kB inhibitor, MG132 that suppresses NF-kB activity at more than 10 mM (Fiedler et al. 1998) suppresses IL-2-induced activation of STAT5 at 50 mM. (Yu and Malek., 2001). However, MG-132 did not decrease the effect of TNF-α on AP-1 activation (Fiedler, Wernke-Dollries and Stark, 1998).

A representative NF-kB inhibitor, DHMEQ (1μg/mL) blocked phytohaemagglutinin (PHA-)-induced nuclear translocation of NF-kB in Jurkat cells via inhibition of degradation of IkBa. Preincubation of peripheral blood mononuclear cells and Jurkat cells with DHMEQ (1 μg/ml, 3 hr) greatly reduced PHA-stimulated expression of IFN-, IL-2 and TNF- genes although DHMEQ alone without PHA-stimulation did not affect cytokine production in unstimulated PBMC. DHMEQ (0·5–3 μg/mL, 3 days) inhibited PHA-stimulated proliferation of peripheral blood mononuclear cells (PBMC) in a dose-dependent manner although did not affect the viability of resting PBMC under identical culture conditions. DHMEQ (3 μg/mL, 24 hr) induced apoptosis of PHA-stimulated PBMC. DHMEQ (0·5 μg/mL) decreased levels of TNF-α-stimulated expression of CD40 in monocyte-derived dendritic cells (DCs). Exposure of DCs to DHMEQ (0·5 or 1 μg/ml) reduced their endocytic ability (Nishioka et al., 2008).

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 (1 mg/kg) inhibits T-cell function versus infective antigenic stimuli 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