Regulation of hypoxia-inducible factor-1 alpha by NF-kappa B

HIF (hypoxia-inducible factor) is the main transcription factor activated by low oxygen tensions. HIF-1 alpha (and other a subunits) is tightly controlled mostly at the protein level, through the concerted action of a class of enzymes called PHDs (prolyl hydroxylases) 1, 2 and 3. Most of the knowledge of HIF derives from studies following hypoxic stress; however, HIF-1 alpha stabilization is also found in non-hypoxic conditions through an unknown mechanism. In the present study, we demonstrate that NF-kappa B (nuclear factor kappa B) is a direct modulator of HIF-1 alpha expression. The HIF-1 alpha promoter is responsive to selective NF-kappa B subunits. siRNA (small interfering RNA) studies for individual NF-kappa B members revealed differential effects on HIF-1 alpha mRNA levels, indicating that NF-kappa B can regulate basal HIF-1 alpha expression. Finally, when endogenous NF-kappa B is induced by TNF alpha (tumour necrosis factor alpha) treatment, HIF-1 alpha levels also change in an NF-kappa B-dependent manner. In conclusion, we find that NF-kappa B can regulate basal TNF alpha and, in certain circumstances, the hypoxia-induced HIF-1 alpha.