Toxin-induced resistance in Bacillus anthracis lethal toxin-treated macrophages
| Autor: | Isabelle I. Salles, Daniel E. Voth, Amy E. Tucker, Jimmy D. Ballard |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Programmed cell death
Proteasome Endopeptidase Complex Receptors Peptide MAP Kinase Signaling System Bacterial Toxins Drug Resistance CHO Cells Biology medicine.disease_cause Cell Line Mice Multienzyme Complexes Cricetinae medicine Extracellular Animals Receptor Protein kinase A Antigens Bacterial Multidisciplinary Toxin Kinase Ubiquitin Macrophages Cell Cycle Biological Sciences biology.organism_classification Molecular biology Bacillus anthracis Cell biology Cysteine Endopeptidases Mutation Signal transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 100(21) |
| ISSN: | 0027-8424 |
| Popis: | In the current study, we show that macrophages adaptively resist anthrax lethal toxin (LT) through a toxin-activated process termed toxin-induced resistance (TIR). TIR was triggered by pretreatment of RAW 264.7 or J774A.1 macrophages with a low dose of LT for at least 6 h, which resulted in resistance to high doses of LT for 96 h. Activation of TIR required functional toxin, because LT subunits, mutants, and heat-inactivated toxin were unable to trigger resistance. TIR macrophages were not altered in toxin receptor levels or cell cycle profiles. Treatment of TIR macrophages with high doses of LT resulted in a sustained decline in full-length mitogen-activated protein kinase kinase 2, a known target of lethal factor, and a marked reduction in diphosphorylated extracellular response kinases 1,2 for 24 h. However, despite the sustained loss of full-length mitogen-activated protein kinase kinase 2, by 48 h, TIR macrophages regained diphosphorylated extracellular response kinases 1,2, suggesting an adaptation led to recovery of this signaling pathway. TIR macrophages were also able to maintain normal levels of ubiquitinylated proteins, whereas sensitive cells show a rapid reduction in ubiquitin-modified proteins before cell death, indicating a possible alteration in proteasome activity contributed to resistance. These results provide a paradigm for toxin-cell interactions and suggest macrophages are capable of adapting to and tolerating toxic doses of LT. |
| Databáze: | OpenAIRE |
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