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

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Title Leishmania donovani Suppresses Activated Protein 1 and NF-�B
Activation in Host Macrophages via Ceramide Generation:
Involvement of Extracellular Signal-Regulated Kinase
 
Creator Ghosh, Sanjukta
Bhattacharyya, Sandip
Sirkar, Madhumita
Sa, Gouri Shankar
Das, Tanya
Majumdar, Debashis
Roy, Syamal
Majumdar, Subrata
 
Subject Infectious Diseases and Immunology
 
Description 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-�B transactivation. Pharmacological inhibition of ceramide synthesis by Fumonisin B1 restored the
induction of AP-1 and NF-�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-�B DNAbinding
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-�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
 
Publisher American Society for Microbiology
 
Date 2002
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/542/1/INFECTION_AND_IMMUNITY_70(12)6828%2D6838_;2002[7].pdf
Ghosh, Sanjukta and Bhattacharyya, Sandip and Sirkar, Madhumita and Sa, Gouri Shankar and Das, Tanya and Majumdar, Debashis and Roy, Syamal and Majumdar, Subrata (2002) Leishmania donovani Suppresses Activated Protein 1 and NF-�B Activation in Host Macrophages via Ceramide Generation: Involvement of Extracellular Signal-Regulated Kinase. Infection and Immunity, 70 (12). pp. 6828-6838.
 
Relation http://dx.doi.org/10.1128/IAI.70.12.6828–6838.2002
http://www.eprints.iicb.res.in/542/