Disease relevance of IRAK3

• Moreover, blood monocytes from patients with chronic myeloid leukemia and patients with metastasis also overexpressed IRAK-M [1].
• Upregulation of TNF-alpha production signaling pathways in monocytes from patients with advanced cirrhosis: possible role of Akt and IRAK-M [2].
• The observed rise of IRAK-M transcription in the human endotoxemia model appeared much greater compared with in vitro-stimulated whole blood [3].

High impact information on IRAK3

• The induction of IRAK-M by hyaluronan and tumor cells was abolished by incubation with anti-CD44 or anti-TLR4 blocking Abs [1].
• Altogether, our findings indicate that deactivation of human monocytes in the presence of tumor cells involves IRAK-M up-regulation, and this effect appears to be mediated by hyaluronan through the engagement of CD44 and TLR4 [1].
• Furthermore, down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates both TNF-alpha mRNA expression and protein production in human monocytes re-exposed to a tumor cell line [1].
• By contrast, another IRAK family member, IRAK-M, negatively regulates this pathway, and is up-regulated in cultures of endotoxin-tolerant monocytes and in monocytes from septic patients within the timeframe of tolerance [1].
• IRAK-M was induced in monocytes upon coculturing with different tumor cells, as well as by fixed tumor cells and medium supplemented with the supernatant from tumor cell cultures [1].

Biological context of IRAK3

• Conclusions: This study showed that the mechanism of endotoxin tolerance exists in the intrahepatic biliary tree and is possibly induced by the expression of IRAK-M in the intrahepatic biliary epithelium, suggesting that the endotoxin tolerance is important in maintaining innate immune biliary homeostasis [4].
• These IRAK-M molecules show 71% sequence identity, a comparable cellular expression, and functional similarities with respect to signal transduction capacity and kinase activity, suggesting functional homology in signalling in human and mouse cells [5].
• To investigate whether polymorphisms in these genes were associated with asthma or asthma-related phenotypes, we screened these genes for polymorphisms by direct sequencing of 24 asthmatics and identified 19 variants in IRAK-M and 12 variants in SIGIRR [6].
• None of the alleles or haplotypes of IRAK-M and SIGIRR were associated with asthma susceptibility or asthma-related phenotype [6].

Anatomical context of IRAK3

• In this study, we show that IRAK-M expression is enhanced at the mRNA and protein level in human monocytes cultured in the presence of tumor cells [1].
• Moreover, immunohistochemistry revealed that IRAK-M was diffusely expressed in intrahepatic bile ducts [4].
• Endotoxin tolerance in human intrahepatic biliary epithelial cells is induced by upregulation of IRAK-M [4].

Associations of IRAK3 with chemical compounds

• In cirrhotic monocytes, LPS-induced TNF-alpha hyperproduction and signaling upregulation were associated with a lack of IRAK-M induction [2].
• Nitric oxide activates the expression of IRAK-M via the release of TNF-alpha in human monocytes [7].

Regulatory relationships of IRAK3

• Furthermore, the expression of IRAK-M induced by GSNO was inhibited by the presence of a blocking antibody raised against TNF-alpha [7].

Other interactions of IRAK3

• The latter include induction of IRAK-M and suppressor of cytokine-signaling-1 (SOCS-1), phosphoinositide-3-kinase (PI3K) signaling, and increased or maintained expression of inhibitor-kappaB (IkappaB) isoforms [8].

References