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The curative effect of fucoidan on visceral leishmaniasis is mediated by activation of MAP kinases through specific protein kinase C isoforms

Cellular & Molecular Immunology volume 11, pages 263–274 (2014)Cite this article

Abstract

Fucoidan can cure both antimony-sensitive and antimony-resistant visceral leishmaniasis through immune activation. However, the signaling events underlying this cellular response remain uncharacterized. The present study reveals that fucoidan induces activation of p38 and ERK1/2 and NF-κB DNA binding in both normal and Leishmania donovani-infected macrophages, as revealed by western blotting and electrophoretic mobility shift assay (EMSA), respectively. Pharmacological inhibition of p38, ERK1/2 or the NF-κB pathway markedly attenuated fucoidan-induced pro-inflammatory cytokine synthesis and inducible nitric oxide synthase (iNOS) gene transcription, resulting in a reduction of parasite clearance. To decipher the underlying mechanism of fucoidan-mediated parasite suppression, the expression and functionality of various protein kinase C (PKC) isoforms were evaluated by immunoblotting and enzyme activity assay. Fucoidan elicited an increase in expression and activity of PKC-α, -βI and -βII isoforms in infected macrophages. Functional knockdown of PKC-α and -β resulted in downregulation of p38 and ERK1/2, along with a marked reduction of IL-12 and TNF-α production in fucoidan-treated infected macrophages. Collectively, these results suggest that the curative effect of fucoidan is mediated by PKC-dependent activation of the mitogen-activated protein kinase (MAPK)/NF-κB pathway, which ultimately results in the production of nitric oxide (NO) and disease-resolving pro-inflammatory cytokines.

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Acknowledgements

This work was supported by the Network Project (BSC 0206), a Supra Institutional Project (BSC 0114) grant of the Council of Scientific and Industrial Research and the J C Bose Fellowship (DST), Government of India.

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Author notes

  1. Susanta Kar

    Present address: * Present address: Section MIG (Microbiology, Immunology, Glycobiology), Department of Laboratory Medicine, Lund University, Lund, Sweden.,

  2. Gunjan Sharma

    Present address: # Present address: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, India.,

Authors and Affiliations

  1. Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India

    Gunjan Sharma, Susanta Kar, Writoban Basu Ball & Pijush K Das

  2. Department of Biochemistry, Calcutta University, Kolkata, India

    Kuntal Ghosh

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Correspondence to Pijush K Das.

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Sharma, G., Kar, S., Basu Ball, W. et al. The curative effect of fucoidan on visceral leishmaniasis is mediated by activation of MAP kinases through specific protein kinase C isoforms. Cell Mol Immunol 11, 263–274 (2014). https://doi.org/10.1038/cmi.2013.68

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