title: PKCδ regulates IL-12p40/p70 production by macrophages and dendritic cells, driving a type 1 healer phenotype in cutaneous leishmaniasis.
abstract: The protein kinase C (PKC) family is involved in the regulation of many intracellular signalling pathways. Here, we report that the PKCδ isoform regulates IL-12p40/p70 production in macrophages and DC and that PKCδ deficiency in mice transforms the 129/Sv healer to a non-healer strain during cutaneous leishmaniasis. Leishmania major-infected PKCδ(-/-) 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, PKCδ(-/-) mice failed to develop delayed-type hypersensitivity responses against Leishmania antigen. PKCδ(-/-) 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-γ by antigen-specific stimulated CD4(+) T cells isolated from popliteal lymph nodes of L. major-infected PKCδ(-/-) mice, explaining the "non-healer" phenotype. We conclude from these data that PKCδ is a regulator of IL-12p40/p70 production by DC and macrophages, driving the healer phenotype during cutaneous leishmaniasis.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB) and Institute of Infectious Diseases and Molecular Medicine (IIDMM), Division of Immunology, Health Science Faculty, University of Cape Town, Cape Town, South Africa.
authors.forename: Reto
authors.initials: R
authors.lastname: Guler
authors.forename: Mona
authors.initials: M
authors.lastname: Afshar
authors.forename: Berenice
authors.initials: B
authors.lastname: Arendse
authors.forename: Suraj P
authors.initials: SP
authors.lastname: Parihar
authors.forename: Melanie
authors.initials: M
authors.lastname: Revaz-Breton
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Anita
authors.initials: A
authors.lastname: Schwegmann
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D004195:Disease Models, Animal; D006968:Hypersensitivity, Delayed; D018664:Interleukin-12 / Q000096:biosynthesis*; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis*; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000201:enzymology* / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D051745:Protein Kinase C-delta / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013045:Species Specificity; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D053762:Interleukin-12 Subunit p40; D018664:Interleukin-12; D051745:Protein Kinase C-delta