X-linked inhibitor of apoptosis protein regulates human interleukin-6 in umbilical vein endothelial cells via stimulation of the nuclear factor-kappaB and MAP kinase signaling pathways.
X-linked inhibitior of apoptosis (XIAP) is known as a potent inhibitor of apoptosis, but more recently has been shown to also act as a modulator of the nuclear factor kB (NF-kappaB) signaling pathway. To investigate whether XIAP also affects other signalling pathways, we studied the transcriptional regulation of interleukin 6 (IL-6), a gene that is strongly affected by XIAP, in more detail. The human IL-6 gene contains transcription factor binding sites for activator protein 1 (AP1), enhancer binding protein beta (C/EBP-beta) and NF-kappaB. In reporter gene assays, mutation of these binding sites revealed the necessity of functional NF-kappaB and AP1-sites for its ability to respond to XIAP. In contrast, IL-6 promoter activity was slightly increased in the C/EBP deletion mutant. Pharmacologic inhibition of extracellular signal regulated kinase (ERK) kinases (MEK1/2) as well as inhibition of the p38 signaling pathway both reduced XIAP-induced IL-6 promoter activity. In conclusion, these results suggest that XIAP regulates IL-6 transcription via NF-kappaB in cooperation with AP1 and C/EBP-beta.
Resch
Ulrike
U
Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Lazarettg. 19, A-1090 Vienna, Austria. ulrike.resch@meduniwien.ac.at
Winsauer
Gabriele
G
Hofer-Warbinek
Renate
R
de Martin
Rainer
R
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic; D014471:Umbilical Veins / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D015850:Interleukin-6; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D051636:X-Linked Inhibitor of Apoptosis Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases