title: 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.
abstract: 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, we present evidence that interferon regulatory factor-1 (IRF-1) and caspase-11 are the essential molecules in activation-induced cell death of microglial cells. The apoptogenic action of inflammatory stimuli such as lipopolysaccharide (LPS) and interferon-gamma (IFNgamma) was mediated through the induction of IRF-1 and caspase-11 expression in two separate events. Although IRF-1 was required for NO synthesis, caspase-11 induction was necessary for NO-independent apoptotic pathway. Microglial cells from IRF-1-deficient mice showed markedly decreased NO production, and they were partially resistant to apoptosis in response to LPS/IFNgamma but were sensitive to NO donor exposure. LPS/IFNgamma 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 caspase inhibitors rendered microglial cells partially resistant to LPS/IFNgamma-induced apoptosis. Inhibition of both NO synthesis and caspase-11 completely blocked LPS/IFNgamma-induced cytotoxicity. These results indicated that LPS/IFNgamma not only induced the production of cytotoxic NO through IRF-1 but also initiated the NO-independent apoptotic pathway through the induction of caspase-11 expression.
authors.affiliation: Graduate School of East-West Medical Science, Kyunghee University, Seoul 130-701, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Hur
authors.forename: P
authors.initials: P
authors.lastname: Lee
authors.forename: J Y
authors.initials: JY
authors.lastname: Kim
authors.forename: N
authors.initials: N
authors.lastname: Cho
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.forename: M S
authors.initials: MS
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Suk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D007249:Inflammation; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D010750:Phosphoproteins; D011994:Recombinant Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma; C505409:Casp3 protein, mouse; C101136:Casp4 protein, mouse; D053148:Caspase 3; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1