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Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|All life stages||High|
Key Event Description
The initial step in IL-1 signal transduction is a ligand-induced conformational change in the first extracellular domain of the IL-1RI that facilitates recruitment of IL-1RacP (Cavalli, et al. 2015). Through conserved cytosolic regions called Toll- and IL-1R–like (TIR) domains (Radons, et al. 2003), the trimeric complex rapidly assembles two intracellular signaling proteins, myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor–activated protein kinase (IRAK) 4 (Brikos, et al. 2007; Li, et al. 2002). Mice lacking MYD88 or IRAK4 show severe defects in IL-1 signaling (Adachi, et al. 1998; Medzhitov, et al. 1998; Suzuki, et al. 2002). Similarly, humans with mutations in the IRAK4 gene have defects in IL-1RI and Toll-like receptor (TLR) signaling (Picard, et al. 2003). IL-1, IL-1RI, IL-RAcP, MYD88, and IRAK4 form a stable IL-1–induced first signaling module (Brikos, et al. 2007). Moreover, patients with defects in MyD88 gene have an increased susceptibility to pyogenic bacterial infections (Picard, et al. 2010; von Bernuth, et al. 2008). Similarly, MyD88 knockout mice showed fatal mycobacterium tuberculosis infection (Picard, et al. 2010; Scanga, et al. 2004).
How It Is Measured or Detected
The suppressed MyD88 cannnot be measured. Therefore, instead of measuring the suppressed MyD88 signaling, the inhibition can be measured by d quantitating ownstream event, such as phosphorylated NF-kB or the proteins or mRNA of IL-6 , IL-8 or other IL-1–responsive cytokines or COX-2 produced by IL-1 stimulated macrophages or macrophage cell lines in the presence of inhibitors (Ref).
Domain of Applicability
The Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog. https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849
Following either vaccination in adult humans or virus challenge in adult rats, the expression of TLR-pathway and pro-inflammatory genes (for example, TLR7, myeloid differentiation primary response gene 88 (MYD88), retinoic acid inducible gene-I (RIGI), IRF7, IFNB, Janus kinase 2 (JAK2), signal transducer and activator of transcription (STAT3), nuclear factor-κB (NFKB), IFNG and tumour necrosis factor (TNF)) is higher in female than male PBMCs from humans and tissues from rats (Hannah, et al. 2008; Klein, et al. 2010).
Evidence for Perturbation by Stressor
The suppression of Myd88 is mostly caused by the suppressed IL-1 signaling or Toll-like receptor signaling. So far, the chemicals that directly affect this molecule is not known.