Immunological homeostasis is often maintained by counteractive functions of two different cell types or two different receptors signaling through different intermediates in the same cell. One of these signaling intermediates is
protein kinase C (PKC). Ten differentially regulated PKC
isoforms are integral to receptor-triggered responses in different cells. So far, eight PKC
isoforms are reported to be expressed in macrophages. Whether a single receptor differentially uses PKC
isoforms to regulate counteractive effector functions has never been addressed. As CD40 is the only receptor characterized to trigger counteractive functions, we examined the relative role of PKC
isoforms in the CD40-induced macrophage functions. We report that in BALB/c mouse macrophages, higher doses of CD40 stimulation induce optimum phosphorylation and translocation of PKCα, βI, βII, and ε whereas lower doses of CD40 stimulation activates PKCδ, ζ, and λ.
Infection of macrophages with the protozoan parasite Leishmania major impairs PKCα, βI, βII, and ε
isoforms but enhances PKCδ, ζ, and λ
isoforms, suggesting a reciprocity among these PKC
isoforms. Indeed, PKCα, βI, βII, and ε
isoforms mediate CD40-induced p38MAPK phosphorylation,
IL-12 expression, and Leishmania killing; PKCδ and ζ/λ mediate ERK1/2 phosphorylation,
IL-10 production, and parasite growth. Treatment of the susceptible BALB/c mice with the lentivirally expressed PKCδ- or ζ-specific
short hairpin RNA significantly reduces the
infection and reinstates host-protective IFN-γ-dominated T cell response, defining the differential roles for PKC
isoforms in immune homeostasis and novel PKC-targeted immunotherapeutic and parasite-derived immune evasion strategies.