Journal
CELLULAR & MOLECULAR IMMUNOLOGY
Volume 11, Issue 3, Pages 263-274Publisher
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/cmi.2013.68
Keywords
fucoidan; MAPK; NF-kappa B; PKC; visceral leishmaniasis
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Funding
- Network Project [BSC 0206]
- Supra Institutional Project [BSC 0114]
- Council of Scientific and Industrial Research
- J C Bose Fellowship (DST), Government of India
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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-kappa B 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-kappa B 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-alpha, -beta I and -beta II isoforms in infected macrophages. Functional knockdown of PKC-alpha and -beta resulted in downregulation of p38 and ERK1/2, along with a marked reduction of IL-12 and TNF-alpha 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-kappa B pathway, which ultimately results in the production of nitric oxide (NO) and disease-resolving pro-inflammatory cytokines.
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