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

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).