X-linked inhibitor of apoptosis protein regulates human interleukin-6 in umbilical vein endothelial cells via stimulation of the nuclear factor- B 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 (NFB) 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 (C/EBP) and NFB. In reporter gene assays, mutation of these binding sites revealed the necessity of functional NFB 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 NFB in cooperation with AP1 and C/EBP. XIAP, IL-6, promoter, endothelial cells, UO126, SB203580 Abbreviations: AP1 – activator protein1, BIR – baculovirus IAP repeat, C/EBP – CCAAT/enhancer binding protein, ERK – extracellular signal regulated kinase, HUVEC – human umbilical vein endothelial cells, IL-1 – interleukin 1 , IKK – I-kappa B kinase, JNK – N terminal c-Jun kinase, MAPK – mitogen activated protein kinase, NFB – nuclear factor-B, TAK1 – TGF activated kinase1, TGF – transforming growth factor, TNF – tumor necrosis factor, XIAP X – linked inhibitor of apoptosis