Essential role of caspase-11 in activation-induced cell death of rat astrocytes.
We have previously shown that rat astrocytes undergo apoptosis upon inflammatory activation. Nitric oxide (NO) produced by activated astrocytes was the major cytotoxic mediator in this type of autoregulatory apoptosis. However, an inhibitor of nitric oxide synthase did not completely block the apoptosis of activated astrocytes, suggesting the presence of other apoptotic pathways. Here, we present evidence that caspase-11 is an essential molecule in NO-independent apoptotic pathway of activated astrocytes. Inflammatory activation (lipopolysaccharide, interferon-gamma, and tumor necrosis factor-alpha treatment) of rat astrocyte cultures and C6 glioma cells led to the induction of caspase-11 followed by activation of caspases-11, -1, and -3. In contrast, NO donors induced activation of caspase-3 only. Inactivation of caspase-11 by the transfection of dominant negative mutant or treatment with the caspase inhibitors rendered the astrocytes partially resistant to the apoptosis following inflammatory activation, but not NO donor exposure. These results indicate that inflammatory stimuli not only induce the production of cytotoxic NO, but also initiate NO-independent apoptotic pathway through the induction of caspase-11 expression.
Suk
Kyoungho
K
Department of Herbal Pharmacology, Graduate School of East-West Medical Science and Research Institute for Basic Sciences, Kyunghee University, Seoul, Korea. ksuk@khu.ac.kr
Kim
Sun Yeou
SY
Kim
Hocheol
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D001253:Astrocytes / Q000166:cytology* / Q000201:enzymology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D005910:Glioma; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D017931:DNA Primers; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; C491071:Casp4 protein, rat; D020169:Caspases