Modulation of tumor necrosis factor and interleukin-1-dependent NF-kappaB activity by mPLK/IRAK.
The innate immune response is an important defense against pathogenic agents. A component of this response is the NF-kappaB-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-1 receptor-associated kinase (mPLK/IRAK), has been proposed to play an obligate role in promoting IL-1-mediated inflammation. However, it is currently unknown whether mPLK/IRAK catalytic activity is required for IL-1-dependent NF-kappaB activation. The present study demonstrates that mPLK/IRAK catalytic activity is not required for IL-1-mediated activation of an NF-kappaB-dependent signal. Intriguingly, catalytically inactive mPLK/IRAK inhibits type 1 tumor necrosis factor (TNF) receptor-dependent NF-kappaB 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-kappaB-dependent gene expression.
Vig
E
E
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, USA.
Green
M
M
Liu
Y
Y
Donner
D B
DB
Mukaida
N
N
Goebl
M G
MG
Harrington
M A
MA
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015703:Antigens, CD; D007375:Interleukin-1; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases