Hypoxic upregulation of TNF receptor type 2 expression involves NF-IL-6 and is independent of HIF-1 or HIF-2

Tumor necrosis factor (TNF) exerts its biologic activity via two distinct m embrane receptors, TNF receptor type 1 (p55TNFR) and TNF receptor type 2 (p 75TNFR). Whereas the p55TNFR gene is rather constitutively expressed, trans cription of p75TNFR is strongly modulated by a number of stimulatory agents . Experimental evidence suggested the involvement of p75TNFR in endothelial cell activation. Therefore, we have tested the transcriptional activity of p75TNFR under conditions of hypoxia and reoxygenation. Northern blot analy sis revealed that p75TNFR mRNA is upregulated in NIH3T3 cells under hypoxia and reoxygenation. This observation directly originates from transcription al activation of the p75TNFR gene, as shown by reporter gene analysis. Cotr ansfection experiments clearly showed that the transcriptional induction of the p75TNFR gene is independent of the hypoxia-induced factors, HIF-1 alph a and HIF-2 alpha. Using deletion mutants of the 5'-flanking region of the p75TNFR gene, we were able to identify a putative DNA binding site for the transcription factor nuclear factor-interleukin-6 (NF-IL-6) to be responsib le for the transcriptional upregulation of the p75TNFR gene under condition s of hypoxia and reoxygenation.