The Proinflammatory Cytokine Interleukin 1B 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 1B (IL-1B) induced the expression of ADM mRNA through activation of HIF-1 under normoxic conditions and enhanced the hypoxiainduced expression in the human ovarian carcinoma cell line OVCAR-3. IL-1B significantly increased accumulation and nuclear translocation of HIF-1A under normoxic conditions and amplified hypoxic HIF-1 activation. IL-1B treatment affected neither HIF-1A mRNA levels nor the hydroxylation status of HIF-1A and, thus, stability of the protein. Instead cycloheximide effectively prevented the increase in HIF-1A protein, indicating a stimulatory effect of IL-1B on HIF-1A translation. Finally, treatment of HIF-1A with short interfering RNA revealed a significant role for HIF-1 in the IL-1B– dependent stimulation of ADM expression. (Cancer Res 2005; 65(11): 4690-7)