API

Event: 1573

Key Event Title

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Suppressed MyD88

Short name

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Suppressed MyD88

Biological Context

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Level of Biological Organization
Cellular

Cell term

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Cell term
macrophage


Organ term

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Organ term
immune system


Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
IL-1 inhibition KeyEvent

Stressors

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Name
None

Taxonomic Applicability

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Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI

Life Stages

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Life stage Evidence
All life stages High

Sex Applicability

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Term Evidence
Unspecific High

Key Event Description

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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

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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

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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



None

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.

 


References

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