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Infection and Immunity, December 2002, p. 6828-6838, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6828-6838.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Leishmania donovani Suppresses Activated Protein 1 and NF-{kappa}B Activation in Host Macrophages via Ceramide Generation: Involvement of Extracellular Signal-Regulated Kinase

Sanjukta Ghosh,1 Sandip Bhattacharyya,1 Madhumita Sirkar,1 Gouri Shankar Sa,2 Tanya Das,1 Debashis Majumdar,1 Syamal Roy,3 and Subrata Majumdar1*

Department of Microbiology,1 Department of Animal Physiology, Bose Institute, Calcutta 700 054,2 Indian Institute of Chemical Biology, Calcutta 700 032, India3

Received 17 July 2002/ Accepted 24 August 2002

In vitro infection of murine peritoneal macrophages with the protozoan Leishmania donovani has been found to alter the signaling parameters of the host. The present study indicates that the enhancement of intracellular ceramide level in macrophages after infection is a major event relating to macrophage dysfunction. We have previously demonstrated that increased ceramide synthesis in host macrophages was involved in the dephosphorylation of extracellular signal-regulated kinase (ERK). In the present study, we further show that downregulation of ERK by ceramide was found to be associated with the inhibition of activated protein 1 (AP-1) and NF-{kappa}B transactivation. Pharmacological inhibition of ceramide synthesis by Fumonisin B1 restored the induction of AP-1 and NF-{kappa}B DNA-binding activities in infected BALB/c macrophages. On the contrary, in the case of macrophages from the leishmaniasis-resistant C.D2 mice, L. donovani failed to induce sustained ceramide synthesis. Enhanced mitogen-activated protein kinase phosphorylation, AP-1 and NF-{kappa}B DNA-binding activity, and the generation of nitric oxide (NO) were observed in L. donovani-infected C.D2 macrophages. ERK activation was necessary for the activation of transcription factors AP-1 and NF-{kappa}B, NO generation, and restriction of the parasite burden in the resistant murine host macrophages. Hence, the induction of ceramide synthesis in host macrophages appears to be instrumental and one of the turning points leading to silencing of the macrophage antileishmanial responses.

* Corresponding author. Mailing address: Department of Microbiology, Bose Institute, P1/12, 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.

Editor: W. A. Petri, Jr.

Infection and Immunity, December 2002, p. 6828-6838, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6828-6838.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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