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- The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. 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. 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. IRAKs are membrane proximal putative serine-threonine kinases. Four IRAK family members have been described in humans: IRAK1, IRAK2, IRAKM, and IRAK4. Two are active kinases, IRAK-1 and IRAK-4, and two are inactive, IRAK-2 and IRAK-M, but all regulate the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Some special/significant features of each IRAK family member:
* There is some evidence that IRAK-1 functions in regulating other signaling cascades leading to NF-κB activation. One signaling pathway in particular nerve growth factor (NGF) may be dependent on the function of IRAK-1 in its signaling pathway for its activation and cell survival.
* IRAK-2 has 4 isoforms IRAK-2a, IRAK-2b, IRAK-2c, and IRAK-2d. The latter two have negative feedback in the TLR signaling pathways. IRAK-2a and IRAK-2b positively activate NF-κB/TLR pathway by stimulating LPS.
* IRAK-M is specific to monomyeloic cells (monocytes and macrophages) while the other IRAKs that are ubiquitously expressed. IRAK-M negatively regulates TLR signaling by inhibiting the IRAK-4/IRAK-1 complex
* The newest described IRAK family member, IRAK-4, has been found to be critical for the recruitment of IRAK-1 and for its activation/degradation. IL-1 stimulates IRAK-4 to the IL-1R complex initiating the Toll/IL-1 receptor signaling cascade upstream of IRAKs, so the deletion of IRAK-1 does not abolish the activation of NF-κB and mitogen-activated protein kinase pathways. (en)
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- The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic (en)
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- Interleukin-1 receptor associated kinase (en)
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