Modulation of tumor necrosis factor and interleukin-1-dependent NF-κB activity by mPLK IRAK

The innate immune response is an important defense against pathogenic agents. A component of this response is the NF-kappa B-dependent activation of genes encoding inflammatory cytokines such as interleukin-8 (IL-8) and cell adhesion molecules like E-selectin. Members of the serine/threonine innate immune kinase family of proteins have been proposed to mediate the innate immune response. One serine/threonine innate immune kinase family member, the mouse Pelle-like kinase/human interleukin-l receptor-associated kinase (mPLK/IRAK), has been proposed to play an obligate role in promoting IL-l-mediated inflammation. However, it is currently unknown whether mPLK/IRAK catalytic activity is required for IL-l-dependent NF-kappa B activation. The present study demonstrates that mPLK/IRAK catalytic activity is not required for IL-l-mediated activation of an NF-kappa B-dependent signal. Intriguingly, catalytically inactive mPLK/IRAK inhibits type 1 tumor necrosis factor (TNF) receptor-dependent NF-kappa B activation, The pathway through which mPLK/IRAK mediates this TNF response is TRADD- and TRAF2-independent. Our data suggest that in addition to its role in IL-1 signaling, mPLK/IRAK is a component of a novel signal transduction pathway through which TNF R1 activates NF-kappa B-dependent gene expression.