title: The interleukin-1 receptor-associated kinases: critical regulators of innate immune signalling.
abstract: 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.
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Sinead
authors.initials: S
authors.lastname: Flannery
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bowie
mesh_terms: D000818:Animals; D006801:Humans; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D050835:Interferon Regulatory Factors; D007375:Interleukin-1; D050791:STAT Transcription Factors; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases