conceived and designed the experiments, which were carried out by TR with help from MR-C, except data shown in Conflict of interest The authors declare that they have no conflict of interest. Toll-like receptors detect microorganisms and protect multicellular organisms from infection by inducing the production of pro-inflammatory cytokines and chemokines. TLRs transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family, which PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19828691 consists of four members: IRAK-1, IRAK-2, IRAK-M and IRAK-4. The crystal structure of the MyD88IRAK-4IRAK-2 death domain complex, referred as Myddosome complex, demonstrated their sequential assembly, in which MyD88 recruits IRAK-4 and the MyD88IRAK-4 complex recruits the IRAK-4 substrates IRAK-2 or the related IRAK-1. Subsequently, the IRAK-1/2 form complex with TRAF6 and dissociate from the receptor complex to activate cascades of downstream kinases, leading to the get BAY41-2272 activation of transcription factor NFkB. On the other hand, IRAK-M is believed to function as a negative regulator that prevents the dissociation of IRAK-1/2 from receptor complex, thereby inhibiting downstream signalling. We previously reported the co-existence of the two parallel TLR/IL-1R-mediated NFkB activation: TAK1 dependent and MEKK3 dependent, respectively. The TAK1-dependent pathway leads to IKKa/b phosphorylation and IKKg activation, resulting in classical NFkB activation through IkBa phosphorylation and degradation. The TAK1independent MEKK3-dependent pathway involves IKKg phosphorylation and IKKa activation, which leads to NFkB activation through IkBa phosphorylation and subsequent dissociation from NFkB but without IkBa degradation. While TLR/IL-1R regulates gene transcription, they also induce gene expression by stabilizing otherwise unstable mRNAs of pro-inflammatory genes. Many cytokine and chemokine mRNA exhibit very short half-lives due to the presence of AU-rich sequence elements located within their 30 untranslated regions. Therefore, the regulation of mRNA stability is an important control of inflammatory gene expression. We have previously reported that the kinase activity of IRAK-4 is required for TAK1dependent 
NFkB activation and mRNA stabilization of cytokines and chemokines, but not for MEKK3-dependent NFkB activation. Based on these findings, we propose that IRAK-4 mediates IL-1RTLR-induced receptor-proximal signalling events through its kinase activity to coordinately regulate TAK1-dependent NFkB activation and mRNA stabilization pathways to ensure robust production of cytokines and chemokines during inflammatory response. In addition to mRNA stabilization, TLR signalling is also necessary for efficient and sustained translation of cytokine and chemokine mRNAs Toll-like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL-1Rassociated kinase family. IRAK-1 and IRAK-2, known to form Myddosomes with MyD88 IRAK-4, mediate TLR7-induced TAK1-dependent NFjB activation. IRAK-M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK-M was also able to interact with MyD88IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFjB activation, which is uncoupled from post-transcriptional regulation. As a result, the IRAK-M-dependent pathway only induced expression of genes that are not regulated
