The interleukin-1 receptor-associated kinases: critical regulators of innate immune signalling.

Sinead Flannery, Andrew G Bowie

School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.

Biochemical pharmacology 2010 Dec 15

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The interleukin receptor-associated kinase (IRAK) family are involved in regulating Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways. TLRs are pattern recognition receptors of the innate immune response that are responsible for sensing pathogens and initiating immunity, while IL-1 is one of the key cytokines that mediates inflammation. As such, IL-1/TLR signalling pathways and the IRAK family are critical in anti-pathogen responses, inflammation and autoimmunity. The family comprises of four members, IRAK-1, IRAK-2, IRAK-M (IRAK-3) and IRAK-4, and has a role in both positive and negative regulation of signal transduction. While it was once thought that the family displayed some redundancy, each member of the family is emerging as a distinct and vital contributor to IL-1/TLR signalling mechanisms. Knockout mouse studies have explored the relative contribution of each of the IRAKs in IL-1/TLR signalling, while the recent generation of kinase-inactive knock-in IRAK-4 mice have revealed which of IRAK-4 functions require its kinase activity. IRAK-2, previously thought of as a pseudokinase, has recently been proposed to have kinase activity that is essential for TLR signalling. Not surprisingly given their critical role in IL-1/TLR signalling, the IRAK family members have been implicated in certain disease models including human immunodeficiencies. Thus the potential targeting of these essential protein kinases therapeutically is also discussed. Copyright © 2010 Elsevier Inc. All rights reserved.

Citation

Sinead Flannery, Andrew G Bowie. The interleukin-1 receptor-associated kinases: critical regulators of innate immune signalling. Biochemical pharmacology. 2010 Dec 15;80(12):1981-91