IRAK4 kinase activity is not required for induction of endotoxin tolerance but contributes to TLR2‐mediated tolerance. Issue 2 (21st May 2013)

• Record Type: Journal Article
• Authors: Xiong, Yanbao; Pennini, Meghan; Vogel, Stefanie N.; Medvedev, Andrei E.
• Is Part Of: Journal of leukocyte biology. Volume 94:Issue 2(2013)
• Page Start: 291
• Page End: 300
• Publication Date: 2013-05-21
• Subjects: Toll‐like receptors -- signal transduction -- innate immunity -- inflammation -- lipopolysaccharide; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.0812401
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : IRAK4 kinase‐inactive macrophages exhibit attenuated TLR2‐ and TLR4‐mediated signaling and normal induction of endotoxin tolerance, while TLR2‐mediated homotolerance, and TLR2‐mediated TLR4 heterotolerance, are deficient. Abstract : Prior exposure to LPS induces "endotoxin tolerance" that reprograms TLR4 responses to subsequent LPS challenge by altering expression of inflammatory mediators. Endotoxin tolerance is thought to limit the excessive cytokine storm and prevent tissue damage during sepsis but renders the host immunocompromised and susceptible to secondary infections. Tolerance initiated via one TLR can affect cellular responses to challenge via the same TLR ("homotolerance") or through different TLRs ("heterotolerance"). IRAK4, an essential component of the MyD88‐dependent pathway, functions as a kinase and an adapter, activating subsets of divergent signaling pathways. In this study, we addressed mechanistically the role of IRAK4 kinase activity in TLR4‐ and TLR2‐induced tolerance using macrophages from WT versus IRAK4 KDKI mice. Whereas IRAK4 kinase deficiency decreased LPS signaling, it did not prevent endotoxin tolerance, as endotoxin pretreatment of WT and IRAK4 KDKI macrophages inhibited LPS‐induced MAPK phosphorylation, degradation of IκB‐α and recruitment of p65 to the TNF‐α promoter, expression of proinflammatory cytokines, and increased levels of A20 and IRAK‐M. Pretreatment of WT macrophages with Pam3Cys, a TLR2–TLR1 agonist, ablated p‐p38 and p‐JNK in response to challenge with Pam3Cys and LPS, whereas IRAK4 KDKI macrophages exhibited attenuated TLR2‐elicited homo‐ and heterotolerance at the level of MAPK activation. Thus, IRAK4 kinase activity is not required for the induction of endotoxin tolerance but contributes significantly to TLR2‐elicited homo‐ and heterotolerance.