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Infection and Immunity, March 2001, p. 1499-1507, Vol. 69, No. 3
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.3.1499-1507.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Immunomodulatory Role of Interleukin-10 in Visceral Leishmaniasis: Defective Activation of Protein Kinase C-Mediated Signal Transduction Events

Sandip Bhattacharyya,1 Sanjukta Ghosh,1 Patti L. Jhonson,2 Syamal K. Bhattacharya,2 and Subrata Majumdar1,*

Department of Microbiology, Bose Institute, Calcutta 700 054, India,1 and Department of Surgery, College of Medicine, University of Tennessee, Memphis, Tennessee 381632

Received 24 July 2000/Returned for modification 25 September 2000/Accepted 1 December 2000

Leishmania donovani, an intracellular protozoan parasite, challenges host defense mechanisms by impairing the signal transduction of macrophages. In this study we investigated whether interleukin-10 (IL-10)-mediated alteration of signaling events in a murine model of visceral leishmaniasis is associated with macrophage deactivation. Primary in vitro cultures of macrophages infected with leishmanial parasites markedly elevated the endogenous release 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 macrophage. 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 (O2-) and nitric oxide and the release of murine tumor necrosis factor-alpha were attenuated in response to L. donovani or rIL-10 treatment. On the other hand, preincubation of the infected macrophages with neutralizing anti-IL-10 MAb significantly blocked the inhibition of nitric oxide and murine tumor necrosis factor-alpha release by the infected macrophages. These findings imply that infection with L. donovani induces endogenous secretion of murine IL-10, which in turn facilitates the intracellular survival of the protozoan and orchestrates several immunomodulatory roles via selective impairment of PKC-mediated signal transduction.

* Corresponding author. Mailing address: Department of Microbiology, Bose Institute, P 1/12, C.I.T. Scheme VII M, Calcutta 700 054, India. Phone: 91-33-337-9416. Fax: 91-33-334-3886. E-mail: subrata{at}boseinst.ernet.in.

Infection and Immunity, March 2001, p. 1499-1507, Vol. 69, No. 3
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.3.1499-1507.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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