Interleukin-1 receptor associated kinase
[4] The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes.
[5][4] Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.
They speculated that this kinase was the link between the T cell's transmembrane IL-1 receptor and the cytosolic signalling pathway's downstream components.
The DNA sequence analysis of IRAK's domains revealed many conserved amino acids with the serine/threonine specific protein kinase Pelle in Drosophila, that functions downstream of a Toll receptor.
The proST region also contains two proline (P), glutamic acid (E), serine (S) and threonine (T)-rich (PEST) sequences that are thought to promote the degradation of IRAK-1.
Because IL-1Rs do not possess intrinsic kinase activity, they rely on the recruitment of adaptor molecules, such as IRAKs, to transduce their signals.
Once IκB is removed, the NF-κB proteins p65 and p50 are free to translocate into the nucleus and activate transcription of proinflammatory genes.
PAMPs are conserved motifs associated with microorganisms that are not found in host cells, such as, bacterial lipopolysaccharide (LPS), viral double-stranded RNA, etc.
TLRs are similar to IL-1Rs in that they do not possess intrinsic kinase activity and require adaptor molecules to relay their signals.
TLR7 and TLR9 mediated IFN-α induction requires the formation of a complex consisting of MyD88, TRAF6 and the interferon regulatory factor 7 (IRF7).
It is thought that IRAK-M enhances the binding of MyD88 to IRAK-1 and IRAK-4, preventing IRAK-1 from dissociating from the receptor complex and inducing downstream NF-κB and MAPK signaling.
The alternative NF-κB pathway involves the activation of NF-κN-inducing kinase (NIK) and subsequent phosphorylation of the transcription factors p100/RelB in an IKKα-dependent mechanism.
[22][23] Inflammation signalling is known to be a major factor in many cancer types, and an inflammatory microclimate is a key aspect of human tumours.
IL-1ß, which activates the inflammatory signalling pathway containing IRAKs, is directly involved in tumour cell growth, angiogenesis, invasion, and metastasis.
IRAK-4 inhibiting drugs are thus a potential therapeutic treatment for lymphoid malignancies with the L265P MyD88 mutation, especially in Waldenström's Macroglobulinaemia, in which BTK and IRAK1/4 inhibitors have shown promising but unconfirmed results.
[24] In 2013, Garrett Rhyasen and his colleagues at the University of Cincinnati studied the contribution of active IRAK-1 and IRAK-4 in human myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
[24][25] Autoimmune disorders such as MS, rheumatoid arthritis, lupus and psoriasis are caused by innate immune system deregulation inducing chronic inflammation.
[26] In most cases, inhibition of IRAK-1 and IRAK-4 are suspected to the most effective targets for knockout drugs, as their functions are integral to the cytokine pathways inducing chronic inflammation.
Compromised IRAK-M leads to overproduction of inflammatory cytokines in the lungs, eventually triggering T cell mediated allergic reactions and exacerbation of asthma symptoms.
