The proinflammatory cytokine interleukin 1beta 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 1beta (IL-1beta) 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-1beta significantly increased accumulation and nuclear translocation of HIF-1alpha under normoxic conditions and amplified hypoxic HIF-1 activation. IL-1beta treatment affected neither HIF-1alpha mRNA levels nor the hydroxylation status of HIF-1alpha and, thus, stability of the protein. Instead cycloheximide effectively prevented the increase in HIF-1alpha protein, indicating a stimulatory effect of IL-1beta on HIF-1alpha translation. Finally, treatment of HIF-1alpha with short interfering RNA revealed a significant role for HIF-1 in the IL-1beta-dependent stimulation of ADM expression.