Modulation of tumor necrosis factor and interleukin-1-dependent NF-kappa Bactivity by mPLK IRAK

The innate immune response is an important defense against pathogenic agent s. A component of this response is the NF-kappa B-dependent activation of g enes 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 i mmune response. One serine/threonine innate immune kinase family member, th e mouse Pelle-like kinase/human interleukin-l receptor-associated kinase (m PLK/IRAK), has been proposed to play an obligate role in promoting IL-l-med iated inflammation. However, it is currently unknown whether mPLK/IRAK cata lytic activity is required for IL-l-dependent NF-kappa B activation. The pr esent study demonstrates that mPLK/IRAK catalytic activity is not required for IL-l-mediated activation of an NF-kappa B-dependent signal. Intriguingl y, catalytically inactive mPLK/IRAK inhibits type 1 tumor necrosis factor ( TNF) receptor-dependent NF-kappa B activation, The pathway through which mP LK/IRAK mediates this TNF response is TRADD- and TRAF2-independent. Our dat a suggest that in addition to its role in IL-1 signaling, mPLK/IRAK is a co mponent of a novel signal transduction pathway through which TNF R1 activat es NF-kappa B-dependent gene expression.