Transcription NF-kB signaling pathway
NF-kB signaling pathway
The Nuclear factor kappa B ( NF-kB ) plays a crucial role in immune andinflammatory responses through the regulation of genes encoding pro-inflammatorycytokines, adhesion molecules, chemokines, growth factors and inducible enzymes.Transcription factors of the NF-kB family are activated in response to signalsthat lead to cell growth, differentiation, apoptosis and other events. NF-kB isactivated by signals that activate Nuclear factor NF-kappa-B inhibitor kinase (IKK ) resulting in the phosphorylation of Nuclear factor of kappa lightpolypeptide gene enhancer in B-cells inhibitor ( I-kB ), this targets I-kBfor degradation in the proteasome and frees the NF-kB dimer, which thentranslocates to the nucleus and activates target genes [1].
Tumor necrosis factor ( TNF-alpha ) activates NF-kB via canonicalphosphorylation of IKK mediated by TNFRSF1A-associated via death domain (TRADD )/ TNF receptor-associated factor 2 ( TRAF2 )/ Mitogen-activatedprotein kinase kinase kinase 14 ( NIK(MAP3K14) ) [2]. Thenon-canonical pathway of NF-kB activation is utilized in response to the ligationof only certain TNF receptor superfamily members, for example Lymphotoxin betareceptor ( LTBR(TNFRSF3) ). In the non-canonical pathway, TRAF stimulatesNIK, which subsequently activates IKK-alpha by phosphorylation.IKK-alpha promotes the processing of nuclear factor of kappa light polypeptidegene enhancer in B-cells 2 ( NF-kB2 (p100) ) from p100 to p52 form. Furtherprocessed NF-kB2 is bound to V-rel reticuloendotheliosis viral oncogene homolog B( RelB ). NF-kB p52/RelB dimer is translocated into the nucleus to affectgene transcription. The non-canonical pathway is independent on IKK-beta andIKK-gamma [3], [1].
T cell receptor ( TCR ) and CD28 molecule ( CD28 ) can stimulateNF-KB via Protein kinase C theta ( PKC-theta )-dependent pathway [4], [5], [6]. Also CD28 triggers V-akt murinethymoma viral oncogene homolog 1 ( AKT )-mediated pathway [5].
Upon binding of Interleukin 1 ( IL-1 ), the Interleukin 1 receptor type I (IL-1RI ) associates with Interleukin 1 receptor accessory protein ( IL1RAP), forming a functional signaling receptor complex that recruits myeloid differentiationprimary response gene 88 ( MyD88 ). This leads to the translocation into thiscomplex of Interleukin-1 receptor-associated kinase ( IRAK1/2 ) together with Tollinteracting protein ( TOLLIP ). IRAK1 binds TNF receptor-associated factor6 ( TRAF6 ). After dissociation from the receptor complex, IRAK1/TRAF6 induces NIK or Mitogen-activated protein kinase kinase kinase 1 (MEKK1(MAP3K1) )-dependent phosphorylation of IKK [7].
Lipopolysacccharide ( LPS ) in complex with Lipopolysaccharide binding protein( LBP ) binds CD14 molecule ( CD14 ) on the cell membrane. It transfersLPS to lymphocyte antigen 96 ( MD- 2 ) and Toll-like receptor 4 (TLR4 ). TLR4 via binding MyD88 [7] and/or possiblyReceptor-interacting serine-threonine kinase 2 ( RIPK2 ) induces NF-kB-activating cascade [8].
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