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IFN Regulatory Factor-2 Regulates Macrophage Apoptosis through a STAT1/3- and Caspase-1-Dependent Mechanism¹

Natalia Cuesta^*, Quan M. Nhu^*, Enrique Zudaire, Swamy Polumuri^*, Frank Cuttitta and Stefanie N. Vogel^2,*

^* Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD 21201; and Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

IFN regulatory factor (IRF)-2^–/– mice are significantly more resistant to LPS challenge than wild-type littermates, and this was correlated with increased numbers of apoptotic Kupffer cells. To assess the generality of this observation, and to understand the role of IRF-2 in apoptosis, responses of peritoneal macrophages from IRF-2^+/+ and IRF-2^–/– mice to apoptotic stimuli, including the fungal metabolite, gliotoxin, were compared. IRF-2^–/– macrophages exhibited a consistently higher incidence of apoptosis that failed to correlate with caspase-3/7 activity. Using microarray gene expression profiling of liver RNA samples derived from IRF-2^+/+ and IRF-2^–/– mice treated with saline or LPS, we identified >40 genes that were significantly down-regulated in IRF-2^–/– mice, including Stat3, which has been reported to regulate apoptosis. Compared with IRF-2^+/+ macrophages, STAT3 mRNA was up-regulated constitutively or after gliotoxin treatment of IRF-2^–/– macrophages, whereas STAT3 mRNA was down-regulated. Phospho-Y705-STAT3, phospho-S727-STAT1, and phospho-p38 protein levels were also significantly higher in IRF-2^–/– than control macrophages. Activation of the STAT signaling pathway has been shown to elicit expression of CASP1 and apoptosis. IRF-2^–/– macrophages exhibited increased basal and gliotoxin-induced caspase-1 mRNA expression and enhanced caspase-1 activity. Pharmacologic inhibition of STAT3 and caspase-1 abolished gliotoxin-induced apoptosis in IRF-2^–/– macrophages. A novel IFN-stimulated response element, identified within the murine promoter of Casp1, was determined to be functional by EMSA and supershift analysis. Collectively, these data support the hypothesis that IRF-2 acts as a transcriptional repressor of Casp1, and that the absence of IRF-2 renders macrophages more sensitive to apoptotic stimuli in a caspase-1-dependent process.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI18797 (to S.N.V.).

² Address correspondence and reprint requests to Dr. Stefanie N. Vogel, Department of Microbiology and Immunology, University of Maryland, 660 West Baltimore Street, Suite 324, Baltimore, MD 21201. E-mail address: svogel{at}som.umaryland.edu

³ Abbreviations used in this paper: IRF, IFN regulatory factor; HPRT, hypoxanthine-guanine phosphoribosyltransferase; ISRE, IFN-stimulated response element; Ct, cycle threshold.

⁴ The online version of this article contains supplemental material.

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