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Act Together to Induce the Cellular Inhibitor of Apoptosis-2 Gene and Prevent Apoptosis in a Variety of Cell Types
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-
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- 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)-
B sites that have been shown to be required for transcriptional activation by TNF-. 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- 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-B sites were retained in the truncated and mutant c-IAP2 promoter constructs, dexamethasone did not inhibit the TNF- induction of luciferase activity, indicating that GR repression through the NF-B sites did not occur. Regulation of the c-IAP2 gene is therefore unique, as GR and NF-B signaling pathways are usually mutually antagonistic, not cooperative. Treatment of A549 cells with TNF- and/or dexamethasone had no effect on cell death, but the two agents were able to inhibit interferon-
/anti-FAS antibody-mediated apoptosis. In human glioblastoma A172 cells, TNF- 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- 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- 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- correlates with the ability of these agents to inhibit apoptosis in a variety of cell types.
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