Upstream eventInhibition, Nuclear factor kappa B (NF-kB)
Impaired T cell activation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of IL-1 signaling||adjacent||High||High|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
Life Stage Applicability
|Not Otherwise Specified||High|
Key Event Relationship Description
Evidence Supporting this KER
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, PKCu activation 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 IKKg and phosphorylation of IKKbby TGF-b activated kinase (TAK1), activating IKKb. IKKb then 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).
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 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).
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).
In Balb/c mice (p.o.) treated with naringin (20, 40 and 80 mg/kg) for 14 days, compared with the vehicle-treated and arthritic-control mice, the naringin treatment demonstrated a considerable decrease in the level of T cells, CD4+GITR+, Th1 cytokine and inflammatory mediator expressions. In contrast, naringin treatment resulted in significantly up-regulated Treg and Th2 cytokine levels (Ahmad et al., 2014).
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 miceand IL-1R type I-deficient mice, exhibited reduced proliferative responses against antigen. These data suggest that IL-1 possesses dual functions during the DTH response. IL-1bis 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
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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.