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.