Protein kinase C delta is essential for optimal macrophage-mediated phagosomal containment of Listeria monocytogenes.
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-gamma and TNF in the macrophage activation pathway required for bacterial killing. Comparison of microarray expression profiles of Listeria 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, PKCdelta, had higher mRNA levels in the LM-infected NF-IL6-deficient macrophages as compared with WT. To define the role of PKCdelta during listeriosis, we infected PKCdelta-deficient mice with LM. PKCdelta-deficient mice were highly susceptible to LM infection with increased bacterial burden and enhanced histopathology despite enhanced NF-IL6 mRNA expression. Subsequent studies in PKCdelta-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 PKCdelta as a critical factor for confinement of LM within macrophage phagosomes.
Schwegmann
Anita
A
Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
Guler
Reto
R
Cutler
Antony J
AJ
Arendse
Berenice
B
Horsnell
William G C
WG
Flemming
Alexandra
A
Kottmann
Andreas H
AH
Ryan
Gregory
G
Hide
Winston
W
Leitges
Michael
M
Seoighe
Cathal
C
Brombacher
Frank
F
D000818:Animals; D001483:Base Sequence; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology* / Q000472:pathogenicity; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010588:Phagosomes / Q000276:immunology* / Q000382:microbiology*; D051745:Protein Kinase C-delta / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics
D022782:CCAAT-Enhancer-Binding Protein-beta; D017931:DNA Primers; D015850:Interleukin-6; D012333:RNA, Messenger; D051745:Protein Kinase C-delta