Prior exposure to LPS induces “endotoxin tolerance” that reprograms TLR4 responses to subsequent LPS challenge by altering expression of inflammatory mediators. Endotoxin tolerance limits the excessive cytokine storm and prevent tissue damage during sepsis, but renders the host immunocompromised and susceptible to secondary infections. IRAK4 acts 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 the induction of TLR4 and TLR2 tolerance using macrophages from wild-type (WT) vs. IRAK4 kinase-dead knock-in (IRAK4KDKI) mice. Pretreatment of WT and IRAK4KDKI macrophages with LPS similarly inhibited LPS-induced degradation of IRAK1 and IκB-α, MAPK phosphorylation, induction of proinflammatory cytokines, and up-regulated expression of negative regulators of TLR signaling, A20 and IRAK-M. Prior exposure of WT macrophages with Pam3Cys, a TLR2-TLR1 agonist, ablated p38 and JNK phosphorylation in response to subsequent challenges with Pam3Cys or LPS. In contrast, IRAK4KDKI macrophages exhibited attenuated TLR2-elicited homo- and heterotolerance at the level p38 and JNK activation. Thus, IRAK4 kinase activity is not required for the induction of endotoxin tolerance, but significantly contributes to TLR2-elicited homo- and heterotolerance.
- Copyright © 2013 by The American Association of Immunologists, Inc.