IL-1R-associated kinases (IRAKs) are important mediators of MyD88-dependent 
signaling by the TLR/IL-1R superfamily and facilitate inflammatory responses. 
IRAK4 and IRAK1 function as active kinases and as scaffolds for protein-protein 
interactions. We report that although IRAK1/4 kinase activity is essential for 
human plasmacytoid dendritic cell (pDC) activation, it is dispensable in B, T, 
dendritic, and monocytic cells, which is in contrast with an essential active 
kinase role in comparable mouse cell types. An IRAK1/4 kinase inhibitor 
abrogated TLR7/9-induced IFN-α responses in both mouse and human pDCs, but other 
human immune cell populations activated via TLR7/9 or IL-1R were refractory to 
IRAK4 kinase inhibition. Gene ablation experiments using small interfering RNA 
demonstrated an essential scaffolding role for IRAK1 and IRAK4 in 
MyD88-dependent signaling. Finally, we demonstrate that autoimmune patient 
(systemic lupus erythematosus and rheumatoid arthritis) serum activates both pDC 
and B cells, but IRAK1/4 kinase inhibition affects only the pDC response, 
underscoring the differential IRAK1/4 functional requirements in human immune 
cells. These data reveal important species differences and elaborate cell type 
requirements for IRAK1/4 kinase activity.