Dual role of inflammatory stimuli in activation-induced cell death of mouse microglial cells - Initiation of two separate apoptotic pathways via induction of interferon regulatory factor-1 and caspase-11

We have previously shown that mouse microglial cells undergo apoptosis upon inflammatory activation and that nitric oxide (NO) is the major autocrine mediator in this process (Lee, P., Lee, J., Kim, S., Yagita, H., Lee, M. S. , Kim, S. Y., Kim, H., and Suk, K. (2001) Brain Res. 892, 380-385). Here, w e present evidence that interferon regulatory factor-1 (IRF-1) and caspase- 11 are the essential molecules in activation-induced cell death of microgli al cells. The apoptogenic action of inflammatory stimuli such as lipopolysa ccharide (LPS) and interferon-gamma (IFN gamma) was mediated through the in duction of IRF-1 and caspase-11 expression in two separate events. Although IRF-1 was required for NO synthesis, caspase-11 induction was necessary fo r NO-independent apoptotic pathway. Microglial cells from IRF-1-deficient m ice showed markedly decreased NO production, and they were partially resist ant to apoptosis in response to LPS/IFN gamma but were sensitive to NO dono r exposure. LPS/IFN gamma treatment resulted in the induction of caspase-11 followed by activation of caspase-11, -1, and -3. Inactivation of caspase- 11 by the transfection of dominant-negative mutant or treatment with the ca spase inhibitors rendered microglial cells partially resistant to LPS/IFN g amma -induced apoptosis. Inhibition of both NO synthesis and caspase-11 com pletely blocked LPS/IFN gamma -induced cytotoxicity. These results indicate d that LPS/IFN gamma not only induced the production of cytotoxic NO throug h IRF-1 but also initiated the NO-independent apoptotic pathway through the induction of caspase-11 expression.