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Relationship: 1921

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 Impaired 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

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
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Not Otherwise Specified 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

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

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

The general consensus understanding is that engagement of the TCR by major histocompatibility complex (MHC) plus antigen initiates downstream CD3 immunotyrosine activationmotif (ITAM) phosphorylation by the Src family kinases, FYN and leukocyte C-terminal src kinase (LCK). Phosphory- lated CD3 activates the T cell specific tyrosine kinase, zeta-chain associated protein kinase (ZAP-70), which phosphorylates the adapter proteins linker for activation of T cells (LAT) and SH2 domain containing leukocyte protein of 76 kDa (SLP-76), causing SLP-76 to bind to VAV1. The VAV1–SLP76–IL-2-inducible T cell kinase (ITK) complex activates phospholipase (PL)Cg1, generat- ing inositol 1,4,5-tripohosphate (IP3) and diacylglycerol (DAG), which ultimately trigger calcium release and pro- tein kinase (PK)C activation, respectively. Activation of a specific PKC isoform, PKCu, connects the above described TCR proximal signaling events to distal events that ulti- mately lead to NF-kB activation. Importantly, PKCactivation is also driven by engagement of the T cell co-stimulatory receptor CD28 by B7 ligands on antigen- presenting cells (APCs). This molecular interaction activates phosphoinositide 3-kinase (PI3K),inducingtriggers a conformational change, causing CARMA1 to bind to B cell leukemia/lymphoma (BCL10) andmucosa- associated lymphoid tissue lymphoma translocation pro- tein (MALT1), forming the CARMA1-BCL10-MALT1 (CBM) complex. Through a mechanism that may involve TNFreceptor-associatedfactor(TRAF6),bothBCL10and MALT1becomepolyubiquitinated.TheIkBkinase(IKK) complex is then recruited to the CBM complex via the IKKgpolyubiquitin binding motif. This associationleads to polyubiquitination of IKKand phosphorylation of IKKbby TGF-activated kinase (TAK1), activating IKKb. IKKthen phosphorylates inhibitor of kB (IkBa), triggering its proteasomal degradation, enabling nuclear translocationofcanonicalNF-kBheterodimerscomprised of p65 reticuloendotheliosis viral oncogene homolog A (RELA) and p50 proteins. Once in the nucleus, NF-kB governsthetranscriptionofnumerousgenesinvolvedinT cell survival, proliferation, and effectorfunctions(Paul and Schaefer, 2013).

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
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

Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent.  Again, age-dependent difference in IL-1 signaling is not known. 

The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).

These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.

References

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

Ahmad, S.F., Zoheir, K.M., Abdel-Hamied, H.E., Ashour, A.E., Bakheet, S.A., Attia, S.M., Abd-Allah, A.R., 2014. Amelioration of autoimmune arthritis by naringin through modulation of T regulatory cells and Th1/Th2 cytokines. Cell Immunol 287, 112-120.

Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.

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.

Nishioka, C., Ikezoe, T., Jing, Y., Umezawa, K., Yokoyama, A., 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.

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.

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.

Paul, S., Schaefer, B.C., 2013. A new look at T cell receptor signaling to nuclear factor-kappaB. Trends Immunol 34, 269-281.

Pordanjani, S.M., Hosseinimehr, S.J., 2016. The Role of NF-kB Inhibitors in Cell Response to Radiation. Curr Med Chem 23, 3951-3963.

Satou, Y., Nosaka, K., Koya, Y., Yasunaga, J.I., Toyokuni, S., Matsuoka, M., 2004. Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. Leukemia 18, 1357-1363.

Wang, Y., Sun, B., Volk, H.D., Proesch, S., Kern, F., 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.

Weih, F., Carrasco, D., Durham, S.K., Barton, D.S., Rizzo, C.A., Ryseck, R.P., Lira, S.A., Bravo, R., 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.