The proinflammatory cytokine interleukin 1β and hypoxia cooperatively induce the expression of adrenomedullin in ovarian carcinoma cells through hypoxia inducible factor 1 activation

Adrenomedullin (ADM) is a potent hypotensive peptide produced by macrophages and endothelial cells during ischemia and sepsis. The molecular mechanisms that control ADM gene expression in tumor cells are still poorly defined. It is known, however, that hypoxia potently increases ADM expression by activation of the transcription factor complex hypoxia inducible factor 1 (HIF-1). Proinflammatory cytokines produced by tumor invading macrophages likewise activate expression of ADM. Herein, we show that apart from hypoxia, the proinflammatory cytokine interleukin 1 beta (1L-1 beta) induced the expression of ADM mRNA through activation of HIF-1 under normoxic conditions and enhanced the hypoxia-induced expression in the human ovarian carcinoma cell line OVCAR-3. IL-1 beta significantly increased accumulation and nuclear translocation of HIF-1 alpha under normoxic conditions and amplified hypoxic HIF-1 activation. IL-1 beta treatment affected neither HIF-1 alpha mRNA levels nor the hydroxylation status of HIF-1 alpha and, thus, stability of the protein. Instead cycloheximide effectively prevented the increase in HIF-1 alpha protein, indicating a stimulatory effect of IL-1 beta on HIF-1 alpha translation. Finally, treatment of HIF-1 alpha with short interfering RNA revealed a significant role for HIF-1 in the IL-1 beta-dependent stimulation of ADM expression.