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Endocrinology Vol. 143, No. 10 3866-3874
Copyright © 2002 by The Endocrine Society

ARTICLE

Dexamethasone and Tumor Necrosis Factor-{alpha} Act Together to Induce the Cellular Inhibitor of Apoptosis-2 Gene and Prevent Apoptosis in a Variety of Cell Types

Jeffrey C. Webster, Reid M. Huber1, Rebecca L. Hanson, Paul M. Collier1, Thomas F. Haws, Juliane K. Mills, Timothy C. Burn1 and Elizabeth A. Allegretto

Departments of Inflammatory Diseases Research (J.C.W., R.L.H., E.A.A.) and Biotechnology (R.M.H., P.M.C., J.K.M., T.C.B.), Bristol-Myers Squibb Pharma, Wilmington, Delaware 19880

Address all correspondence and requests for reprints to: Jeffrey C. Webster, Transtech Pharma, 4170 Mendehall Oaks Parkway, Suite 110, High Point, North Carolina 27265. E-mail: jwebster{at}ttpharma.com.

Using microarray technology, we analyzed 12,000 genes for regulation by TNF-{alpha} and the synthetic glucocorticoid, dexamethasone, in the human lung epithelial cell line, A549. Only one gene was induced by both agents, the cellular inhibitor of apoptosis 2 (c-IAP2), which was induced 17-fold and 5-fold by TNF-{alpha} at 2 h and 24 h, respectively, and increased 14-fold and 9-fold by dexamethasone at 2 h and 24 h, respectively. The combination of the two agents together led to an additive increase (34-fold) at 2 h and a more than additive effect (36-fold) at 24 h. The human c-IAP2 promoter contains two nuclear factor (NF)-{kappa}B sites that have been shown to be required for transcriptional activation by TNF-{alpha}. To test whether glucocorticoids regulate the c-IAP2 gene at the level of the promoter, a reporter vector containing 947 bases upstream of the start site of transcription of the human c-IAP2 promoter was linked to luciferase [IAP(-947–+54)-LUC] and transfected into A549 cells. Dexamethasone and TNF-{alpha} each induced reporter activity, whereas the combination of the two agents led to greater induction of luciferase than either one alone. Truncation of the promoter region containing a putative glucocorticoid response element (GRE) at -515 [IAP(-395–+54)-LUC] or mutation of the GRE in the context of the natural promoter [IAP(-947–+54mutGRE)-LUC] resulted in a loss of dexamethasone-mediated induction of reporter activity. Although the functional NF-{kappa}B sites were retained in the truncated and mutant c-IAP2 promoter constructs, dexamethasone did not inhibit the TNF-{alpha} induction of luciferase activity, indicating that GR repression through the NF-{kappa}B sites did not occur. Regulation of the c-IAP2 gene is therefore unique, as GR and NF-{kappa}B signaling pathways are usually mutually antagonistic, not cooperative. Treatment of A549 cells with TNF-{alpha} and/or dexamethasone had no effect on cell death, but the two agents were able to inhibit interferon-{gamma}/anti-FAS antibody-mediated apoptosis. In human glioblastoma A172 cells, TNF-{alpha} and dexamethasone together elicited a greater than additive increase in c-IAP2 mRNA levels and also inhibited anti-FAS antibody-mediated A172 cell apoptosis. In contrast, in human CEM-C7 leukemic T cells, whereas TNF-{alpha} and dexamethasone treatment also led to an increase in c-IAP2 mRNA, the two agents were able to induce apoptosis on their own. However, TNF-{alpha} and dexamethasone were also able to blunt anti-FAS-induced apoptosis in the T cells. These data indicate that the induction of the antiapoptotic protein, c-IAP2, by glucocorticoids and TNF-{alpha} correlates with the ability of these agents to inhibit apoptosis in a variety of cell types.




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