Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 41, Issue 3, Pages 706-715Publisher
WILEY
DOI: 10.1002/eji.201040985
Keywords
Cytokines; DC; Kinases; Leishmania; Macrophages
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Funding
- Swiss Foundation
- Claude Leon Foundation South Africa
- National Research Foundation (NRF) South Africa
- Medical Research Council (MRC) South Africa
- South African Research Chair Initiative of the Department of Science and Technology (DST)
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The protein kinase C (PKC) family is involved in the regulation of many intracellular signalling pathways. Here, we report that the PKC delta isoform regulates IL-12p40/p70 production in macrophages and DC and that PKC delta deficiency in mice transforms the 129/Sv healer to a non-healer strain during cutaneous leishmaniasis. Leishmania major-infected PKC delta(-/-) 129/Sv mice developed a rapid increase in footpad swelling and parasite burden with disease progression, leading to necrosis and ulceration similar to non-healer BALB/c mice. Moreover, PKC delta (/) mice failed to develop delayed-type hypersensitivity responses against Leishmania antigen. PKC delta(-/-) macrophages were fully functional with normal MHC class II surface expression and GM-CSF production, recruitment to the draining lymph node and killing effector functions by NO production. In contrast, macrophages and DC produced significantly reduced IL-12p40 and IL-12p70 compared to the WT cells. Decreased IL-12 production resulted in diminished Th1 differentiation, as determined by a striking reduction in IFN-gamma by antigen-specific stimulated CD4(+) T cells isolated from popliteal lymph nodes of L. major-infected PKC delta(-/-) mice, explaining the non-healer'' phenotype. We conclude from these data that PKC delta is a regulator of IL-12p40/p70 production by DC and macrophages, driving the healer phenotype during cutaneous leishmaniasis.
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