Immunomodulatory role of interleukin-10 in visceral leishmaniasis: Defective activation of protein kinase C-mediated signal transduction events

Leishmania donovani, an intracellular protozoan parasite, challenges host d efense mechanisms by impairing the signal transduction of macrophages. In t his study we investigated whether interleukin-10 (IL-10)-mediated alteratio n of signaling events in a murine model of visceral leishmaniasis is associ ated with macrophage deactivation. Primary in vitro cultures of macrophages infected with leishmanial parasites markedly elevated the endogenous relea se of IL-10. Treatment with either L. donovani or recombinant IL-10 (rIL-10 ) inhibited both the activity and expression of the Ca2+-dependent protein kinase C (PKC) isoform. However, preincubation with neutralizing anti-IL-10 monoclonal antibody (MAb) restored the PKC activity in the parasitized mac rophage. Furthermore, we observed that coincubation of macrophages with rIL -10 and L. donovani increased the intracellular parasite burden, which was abrogated by anti-IL-10 MAb. Consistent with these observations, generation of superoxide (O-2(-)) and nitric oxide and the release of murine tumor ne crosis factor-cu. were attenuated in response to L. donovani or rIL-10 trea tment. On the other hand, preincubation of the infected macrophages with ne utralizing anti-IL-10 MAb significantly blocked the inhibition of nitric ox ide and murine tumor necrosis factor-or release by the infected macrophages . These findings imply that infection with L. donovani induces endogenous s ecretion of murine IL-10, which in turn facilitates the intracellular survi val of the protozoan and orchestrates several immunomodulatory roles via se lective impairment of PKC-mediated signal transduction.