Rapid up-regulation of IRAK-M expression following a second endotoxin challenge in human monocytes and in monocytes isolated from septic patients

Biochem Biophys Res Commun. 2003 Nov 14;311(2):465-72. doi: 10.1016/j.bbrc.2003.10.019.


The exposure of human monocytes to the gram-negative endotoxin LPS provokes them to enter a transient state in which they are refractory to further stimulation by LPS. This phenomenon is known as 'endotoxin tolerance' (ET) and it is characterized by a decrease in leukocyte proinflammatory cytokine production in response to LPS. In the present study, we have analyzed the expression of IRAK-M mRNA and protein in a human model of ET using human monocytes isolated from peripheral blood. In these monocyte cultures, IRAK-M mRNA was expressed 6h after stimulation with different doses of LPS. However, endotoxin pretreatment induced a more immediate up-regulation of IRAK-M gene expression, transcripts appearing only one hour after a second LPS-challenge, and the production of high levels of IRAK-M protein in these tolerant monocytes. We also analyzed the response of monocytes isolated from septic patients within a temporal tolerance timeframe when stimulated ex vivo with LPS. In contrast to monocytes from healthy volunteers and patients outside of the tolerance timeframe, monocytes from septic patients rapidly expressed IRAK-M mRNA when stimulated with LPS ex vivo. Moreover, the expression of IRAK-M mRNA was more rapidly induced in the presence of a PI3K inhibitor, suggesting a connection between these two kinases. Thus, our data indicate that IRAK-M could play a pivotal role in the process of ET in human monocytes and provide evidence that PI3K is involved in regulating its expression.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Endotoxins / genetics
  • Endotoxins / pharmacology
  • Gene Expression Regulation / genetics
  • Humans
  • Interleukin-1 Receptor-Associated Kinases
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism*
  • Lipopolysaccharides / pharmacology*
  • Middle Aged
  • Protein Kinases / biosynthesis*
  • Protein Kinases / genetics
  • Sepsis / metabolism*
  • Up-Regulation / drug effects*


  • Endotoxins
  • Lipopolysaccharides
  • Protein Kinases
  • IRAK3 protein, human
  • Interleukin-1 Receptor-Associated Kinases