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

• Published in: Cellular & molecular immunology Vol. 11; no. 3; pp. 263 - 274
• Main Authors: Sharma, Gunjan, Kar, Susanta, Basu Ball, Writoban, Ghosh, Kuntal, Das, Pijush K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2014; Nature Publishing Group
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antimony; Biomedicine; Cell Line; C亚型; Electrophoretic mobility; Enzymatic activity; Enzyme Activation - drug effects; Extracellular signal-regulated kinase; Fucoidan; Immune clearance; Immune response; Immunity - drug effects; Immunoblotting; Immunology; Inflammation Mediators - metabolism; Interleukin 12; Isoenzymes - metabolism; Isoforms; Kinases; Leishmania; Leishmania donovani - drug effects; Leishmaniasis, Visceral - drug therapy; Leishmaniasis, Visceral - enzymology; Leishmaniasis, Visceral - immunology; Leishmaniasis, Visceral - parasitology; Macrophages; MAP kinase; MAP Kinase Signaling System - drug effects; MAP激酶; Medical Microbiology; Mice, Inbred BALB C; Microbiology; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - metabolism; NF-κB protein; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Parasitic diseases; Polysaccharides - pharmacology; Polysaccharides - therapeutic use; Protein kinase C; Protein Kinase C - metabolism; Proteins; research-article; Thiazines - pharmacology; Transcription Factor AP-1 - metabolism; Tumor necrosis factor-α; Vaccine; Visceral leishmaniasis; Western blotting; 介导; 促分裂原活化蛋白激酶; 疗效; 蛋白激酶C; 褐藻多糖硫酸酯; 诱导型一氧化氮合酶; NF-κB; PKC; MAPK; fucoidan; visceral leishmaniasis
• ISSN: 1672-7681; 2042-0226; 2042-0226
• DOI: 10.1038/cmi.2013.68

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 ERKI/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, ERKI/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, -β1 and -βⅡ isoforms in infected macrophages. Functional knockdown of PKC-α and -β resulted in downregulation of p38 and ERKI/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.