Suppression of iNOS expression by fucoidan is mediated by regulation of p38 MAPK, JAK/STAT, AP-1 and IRF-1, and depends on up-regulation of scavenger receptor B1 expression in TNF-alpha- and IFN-gamma-stimulated C6 glioma cells.
In neurodegenerative disorders, activated glial cells overproduce nitric oxide (NO), which causes neurotoxicity. Inducible NO synthase (iNOS) is a potential therapeutic target in neurodegenerative diseases. Here, we examined the action of fucoidan, a high-molecular-weight sulfated polysaccharide, on tumor necrosis factor-alpha (TNF-alpha)- and interferon-gamma (IFN-gamma)-induced NO production in C6 glioma cells. Fucoidan suppressed TNF-alpha- and IFN-gamma-induced NO production and iNOS expression. In addition, fucoidan inhibited TNF-alpha- and IFN-gamma-induced AP-1, IRF-1, JAK/STAT and p38 mitogen-activated protein kinase (MAPK) activation and induced scavenger receptor B1 (SR-B1) expression. Blocking of SR-B1 did not reverse the inhibitory effect of fucoidan on TNF-alpha- and IFN-gamma- stimulated NO production. However, inhibition of SR-B1 expression by siRNA increased iNOS expression and p38 phosphorylation in TNF-alpha- and IFN-gamma-stimulated C6 cells. Overall, p38 MAPK, AP-1, JAK/STAT and IRF-1 play an important role in the inhibitory effect of fucoidan on TNF-alpha- and IFN-gamma-stimulated NO production, and intracellular SR-B1 expression may be related to the inhibition of iNOS expression by fucoidan via regulation of p38 phosphorylation. The present results also suggest that fucoidan could be a potential therapeutic agent for treating inflammatory-related neuronal injury in neurological disorders.
Do
Hang
H
Division of Immunopharmacology, College of Pharmacy, Sungkyunkwan University, Suwon, Kyunggi-do, Republic of Korea.
Pyo
Suhkneung
S
Sohn
Eun-Hwa
EH
D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D005910:Glioma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D011134:Polysaccharides / Q000494:pharmacology*; D051381:Rats; D051116:Receptors, Scavenger / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017931:DNA Primers; D011134:Polysaccharides; D051116:Receptors, Scavenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C007789:fucoidan; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases