1. Protein kinase C δ is essential for optimal macrophage-mediated phagosomal containment ofListeria monocytogenes
- Author
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Michael Leitges, Alexandra Flemming, Andreas H. Kottmann, Berenice Arendse, Frank Brombacher, Reto Guler, Anita Schwegmann, Winston Hide, Gregory Ryan, William G. C. Horsnell, Cathal Seoighe, and Antony J. Cutler
- Subjects
In Vitro Techniques ,Biology ,medicine.disease_cause ,Proinflammatory cytokine ,Microbiology ,Mice ,Listeria monocytogenes ,Phagosomes ,Gene expression ,medicine ,Animals ,Macrophage ,Listeriosis ,RNA, Messenger ,Transcription factor ,Protein kinase C ,DNA Primers ,Oligonucleotide Array Sequence Analysis ,Phagosome ,Mice, Knockout ,Multidisciplinary ,Base Sequence ,Interleukin-6 ,CCAAT-Enhancer-Binding Protein-beta ,Macrophages ,Biological Sciences ,Molecular biology ,Protein Kinase C-delta ,Tumor necrosis factor alpha - Abstract
Activation of macrophages and subsequent “killing” effector functions against infectious pathogens are essential for the establishment of protective immunity. NF-IL6 is a transcription factor downstream of IFN-γ and TNF in the macrophage activation pathway required for bacterial killing. Comparison of microarray expression profiles ofListeria monocytogenes(LM)-infected macrophages from WT and NF-IL6-deficient mice enabled us to identify candidate genes downstream of NF-IL6 involved in the unknown pathways of LM killing independent of reactive oxygen intermediates and reactive nitrogen intermediates. One differentially expressed gene, PKCδ, had higher mRNA levels in the LM-infected NF-IL6-deficient macrophages as compared with WT. To define the role of PKCδ during listeriosis, we infected PKCδ-deficient mice with LM. PKCδ-deficient mice were highly susceptible to LM infection with increased bacterial burden and enhanced histopathology despite enhanced NF-IL6 mRNA expression. Subsequent studies in PKCδ-deficient macrophages demonstrated that, despite elevated levels of proinflammatory cytokines and NO production, increased escape of LM from the phagosome into the cytoplasm and uncontrolled bacterial growth occurred. Taken together these data identified PKCδ as a critical factor for confinement of LM within macrophage phagosomes.
- Published
- 2007