In this paper Eduardo Pauls and Sambit Nanda in Philip Cohen's lab have identified unique and distinctive roles for two members of the IRAK sub-family of protein kinases, which suggest that they may be attractive targets for the development of drugs to treat chronic inflammatory and autoimmune diseases.
The lab developed and studied knock-in mice in which wild type IRAK1 was replaced by a mutant devoid of kinase activity. They found that the activation of Toll-Like Receptor 7 (TLR7) and TLR9 by single-stranded RNA or DNA of viral origin, respectively, did not produce interferonÃ_Â_ in plasmacytoid dendritic cells expressing catalytically inactive IRAK1. In contrast, the production of pro-inflammatory cytokines, such as Tumour Necrosis Factor (TNF) and interleukin 6, was similar in macrophages from the IRAK1 knock-in mice and wild type mice after stimulation of TLR7 or other TLRs. The overproduction of type 1 interferons by plasmacytoid dendritic cells resulting from the abnormal activation of TLR9 by 'self' DNA is thought to be a cause of some types of lupus. The new findings therefore suggest that inhibitors of IRAK1 should be evaluated for the treatment this autoimmune disease.
In contrast to IRAK1, IRAK2 is an inactive 'pseudokinase'. A knock-in mouse was therefore made in which wild type IRAK2 was replaced by a mutant in which serine 525 was replaced by alanine to create a mutant that was unable to interact with TRAF6, an E3 ubiquitin ligase required to activate the TLR signaling network. Studies with macrophages from the IRAK2 knock-in mice revealed that the IRAK2-TRAF6 interaction was needed to maintain a low level of activation of the protein kinase IKKÃ_Â_ after prolonged TLR activation, without which the late surge in TNF and IL-6 mRNA production and the secretion of these cytokines did not occur. They found that the time at which IRAK2 function became rate limiting correlated with the time at which the IRAK1 protein was degraded, suggesting that the early phase of TNF and IL-6 mRNA production may be sustained by IRAK1 in the absence of a functional IRAK2. Importantly, the loss of the IRAK2-TRAF6 interaction had little effect on the production of anti-inflammatory molecules, such as interleukin 10 and the protein phosphatase DUSP1, which are produced during the early phase of TLR signaling. These findings suggest that IRAK2 may be an attractive target for the development of drugs to treat chronic inflammatory diseases, such as rheumatoid arthritis, which are caused by the overproduction of TNF and other inflammatory mediators. An advantage of such drugs is that they may only have a minor effect on the production of interleukin 10, which is critical for the resolution of inflammation.
The lab developed and studied knock-in mice in which wild type IRAK1 was replaced by a mutant devoid of kinase activity. They found that the activation of Toll-Like Receptor 7 (TLR7) and TLR9 by single-stranded RNA or DNA of viral origin, respectively, did not produce interferonÃ_Â_ in plasmacytoid dendritic cells expressing catalytically inactive IRAK1. In contrast, the production of pro-inflammatory cytokines, such as Tumour Necrosis Factor (TNF) and interleukin 6, was similar in macrophages from the IRAK1 knock-in mice and wild type mice after stimulation of TLR7 or other TLRs. The overproduction of type 1 interferons by plasmacytoid dendritic cells resulting from the abnormal activation of TLR9 by 'self' DNA is thought to be a cause of some types of lupus. The new findings therefore suggest that inhibitors of IRAK1 should be evaluated for the treatment this autoimmune disease.
In contrast to IRAK1, IRAK2 is an inactive 'pseudokinase'. A knock-in mouse was therefore made in which wild type IRAK2 was replaced by a mutant in which serine 525 was replaced by alanine to create a mutant that was unable to interact with TRAF6, an E3 ubiquitin ligase required to activate the TLR signaling network. Studies with macrophages from the IRAK2 knock-in mice revealed that the IRAK2-TRAF6 interaction was needed to maintain a low level of activation of the protein kinase IKKÃ_Â_ after prolonged TLR activation, without which the late surge in TNF and IL-6 mRNA production and the secretion of these cytokines did not occur. They found that the time at which IRAK2 function became rate limiting correlated with the time at which the IRAK1 protein was degraded, suggesting that the early phase of TNF and IL-6 mRNA production may be sustained by IRAK1 in the absence of a functional IRAK2. Importantly, the loss of the IRAK2-TRAF6 interaction had little effect on the production of anti-inflammatory molecules, such as interleukin 10 and the protein phosphatase DUSP1, which are produced during the early phase of TLR signaling. These findings suggest that IRAK2 may be an attractive target for the development of drugs to treat chronic inflammatory diseases, such as rheumatoid arthritis, which are caused by the overproduction of TNF and other inflammatory mediators. An advantage of such drugs is that they may only have a minor effect on the production of interleukin 10, which is critical for the resolution of inflammation.