In the pathway, NF-κB/Rel proteins are bound and inhibited by IκB proteins. Growth factors, proinflammatory cytokines, chemotherapy, radiotherapy, and antigen receptors activate an IKK complex, which phosphorylates IκB proteins. Phosphorylation of IκB leads to its ubiquitination and proteasomal degradation, freeing NF-κB/Rel complexes. The transcription factor NF-κB is thereby released and promotes the expression of cytokines, cell adhesion molecules, and antiapoptotic proteins. The NF-κB signal transduction pathway in development and dysfunction of the immune system. In NF-κB pathway, most proteins regulate the expression of genes influencing a broad range of biological processes including innate and adaptive immunity, inflammation, stress responses, B-cell development, and lymphoid organogenesis.
Nuclear factor kappa B is a dimer belonging to Rel family, that contains a highly conserved Rel-homology domain (RHD). The NFκB proteins have five different monomers that share a Rel homology domain in their N-terminus. The p105 and p100 which precursors of NFκB1 and NFκB2 that are transformed to mature NFκB subunits (p50 and p52) by the ubiquitin pathway. The nuclear translocation of NFκB, inhibitory kappa B (IκB) proteins, and DNA binding interaction with RHD.
NFκB signalling pathway have two major ways,that as : (1) the canonical (mediated by IκB degradation), and (2) the non-canonical (p100 mediated) pathways. In the cell ,the NFκB dimers are attached to IκB proteins under normal conditions. The canonical pathway will be activated by the inflammatory reaction, for example,interleukins, TNF-α, or LPS, that leads to the activation of the IκB kinase (IKK) complex. Then NFκB becomes free, which follows it moves to the nucleus and initiates transcription of the target genes.
Toll-like receptors(TLRs) are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes. Microbes will be recognized by toll-like receptors when they breach physical barriers such as the skin or intestinal tract mucosa, and the recognization can activate immune cell responses.
TLRs together with the Interleukin-1 receptors form a receptor superfamily, known as the "Interleukin-1 Receptor/Toll-Like Receptor Superfamily". Members of this family share a common TIR (Toll-IL-1 receptor) domain.
TIR domains has three subgroups: subgroup 1 TIR domains, subgroup 2 TIR domains and subgroup 3 TIR domains. Among them, proteins with subgroup 3 TIR domains are exclusively cytosolic and mediate signaling from proteins of subgroups 1 and 2. TLRs usually function as homodimers, for example, TLR2 forms heterodimers with TLR1 or TLR6. TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4's recognition of LPS, which requires MD-2.
TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway. The MyD88-dependent response occurs on dimerization of the TLR receptor, and is utilized by every TLR except TLR3. Its primary effect is activation of NFκB. Ligand binding and conformational change that occurs in the receptor recruits the adaptor protein MyD88. MyD88 then recruits IRAK 4, IRAK1 and IRAK2. IRAK kinases then phosphorylate and activate the protein TRAF6, which in turn polyubiquinates the protein TAK1, as well as itself in order to facilitate binding to IKKβ. On binding, TAK1 phosphorylates IKKβ, which then phosphorylates IκB causing its degradation and allowing NFκB to diffuse into the cell nucleus and activate transcription.
Both TRL3 and TRL4 utilize the TRIF-dependent pathway, which is triggered by dsRNA and LPS, respectively. For TRL3, dsRNA leads to activation of the receptor, recruiting the adaptor TRIF. TRIF activates the kinases TBK1 and RIP1, which creates a branch in the signaling pathway. The TRIF/TBK1 signaling complex phosphorylates IRF3 allowing its translocation into the nucleus and production of Type I interferons. Meanwhile, activation of RIP1 causes the polyubiquination and activation of TAK1 and NFκB transcription in the same manner as the MyD88-dependent pathway.
TLR signaling ultimately leads to the induction or suppression of genes that orchestrate the inflammatory response. Toll-like receptors have also been shown to be an important link between innate and adaptive immunity through their presence in dendritic cells.