Upstream eventInhibition, Nuclear factor kappa B (NF-kB)
Suppression of T cell activation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of IL-1 binding to IL-1 receptor leading to increased susceptibility to infection||adjacent||High||Not Specified|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
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, PKCu, connects the above described TCR proximal signaling events to distal events that ultimately 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). 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 Supporting this KER
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)
Indeed, 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 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).
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-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. These data suggest that IL-1b 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
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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., 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.
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., et al., 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., 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.
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.