Model of IRAK-2 usage in MOLF/Ei compared with C57BL/6J TLR signal transduction. In MOLF/Ei macrophages, knockdown experiments reveal that IRAK-2 plays a central role in activation of p38 and IKK, two pathways which show increased activity relative to C57BL/6J mice. Neither of these phenotypes can be completely recapitulated with the MOLF/Ei allele on a classical inbred background, suggesting that additional MOLF/Ei alleles are important for the complete levels of hyperresponsiveness observed in comparing parental strains. The MOLF/Ei allele of Irak2 expresses less of the IRAK-2C isoform, which may underlie the phenotype by decreasing interference with IRAK-2A activity. In C57BL/6J macrophages, which express an increased amount of IRAK-2C, previous studies have demonstrated that early TLR signaling events are not controlled by IRAK-2, although it is important for late activation of the NF-κB axis.