IRAK-2 and PI 3-kinase synergistically activate NF-kappaB and AP-1.
Antisense interleukin-1 (IL-1) receptor associated kinase-2 (IRAK-2) oligonucleotide (ODN) and antisense p110 PI 3-kinase ODN blocked IRAK-2 and p110 PI 3-kinase expression, respectively. As a result, antisense IRAK-2 ODN or antisense p110 PI 3-kinase ODN inhibited IL-1-induced NF-kappaB and AP-1 activation in HepG2 cells. The inhibition of NF-kappaB activation by antisense IRAK-2 ODN or antisense p110 PI 3-kinase ODN and the inhibition of AP-1 activation by antisense IRAK-2 ODN were incomplete, whereas AP-1 activation could be inhibited by antisense p110 PI 3-kinase ODN completely. These results indicate that IRAK-2 is necessary but insufficient to activate NF-kappaB and AP-1 completely and that although PI 3-kinase is not sufficient for NF-kappaB full activation, it is sufficient to activate AP-1 completely. The effects of IRAK-2 or PI 3-kinase on NF-kappaB and AP-1 activation were confirmed by the results that overexpression of IRAK-2 failed to fully activate NF-kappaB and AP-1 and that overexpression of p110 PI 3-kinase is insufficient for NF-kappaB full activation but sufficient for AP-1 activation. Cotransfection experiments showed that the combination of antisense IRAK-2 ODN and antisense p110 PI 3-kinase ODN resulted in additive inhibition of NF-kappaB as well as AP-1 activation. On the other hand, coexpression of IRAK-2 with p110 PI 3-kinase led to a synergistic activation of NF-kappaB and AP-1. These data suggest that IRAK-2 and PI 3-kinase cooperate to activate NF-kappaB and AP-1.
Guo
F
F
Institute of Pharmaceutic Sciences, The First Military Medical University, Guangzhou, China.
Wu
S
S
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004357:Drug Synergism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D007700:Kinetics; D016328:NF-kappa B / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D018836:Inflammation Mediators; D007375:Interleukin-1; D053592:Interleukin-1 Receptor-Associated Kinases; D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D018808:Transcription Factor AP-1