Human Interleukin-1 Receptor-associated Kinase-2 Is Essential for Toll-like Receptor-mediated Transcriptional and Post-transcriptional Regulation of Tumor Necrosis Factor α

Toll-like receptors (TLRs) are pattern-recognition receptors that recognize microbial ligands and subsequently trigger intracellular signaling pathways involving transcription factors such as NF kappa B and MAPKs such as p38. TLR signaling can regulate both transcriptional and post-transcriptional events leading to altered gene expression and thus appropriate immune responses. The interleukin-1 receptor-associated kinase (IRAK) family comprises four kinases that regulate TLR signaling. However, the role of IRAK-2 has remained unclear, especially in human cells. Recent studies using cells from in-bred Irak2(-/-) mice showed that murine IRAK-2 was not required for early TLR signaling events but had a role in delayed NF kappa B activation and in cytokine production. IRAK-2 in mice has four splice variants, two of which are inhibitory, whereas human IRAK-2 has no splice variants. Thus IRAK-2 in mice and humans may function differently, and therefore we analyzed the role of IRAK-2 in TLR responses in primary human cells. siRNA knockdown of IRAK-2 expression in human peripheral blood mononuclear cells showed a role for human IRAK-2 in both TLR4- and TLR8-mediated early NF kappa B and p38 MAPK activation and in induction of TNF mRNA. These data conflict with findings from the in-bred Irak2(-/-) mice but concur with what has been seen in wild-derived mice for TLR2. Moreover, human IRAK-2 was required for regulating MyD88-dependent TNF alpha mRNA stability via the TNF 3'UTR. Collectively, these data demonstrate for the first time an essential role for IRAK-2 in primary human cells for both transcriptional and post-transcriptional TLR responses.