Oral administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis (EAE) by induction of HSP70 and stabilization of NF-kappaB/IkappaBalpha transcriptional complex.
Available treatments for multiple sclerosis (MS) require frequent injections and have significant side effects. In this study, we examined the immunomodulatory properties of orally administered triptolide, a major diterpenoid triepoxide isolated from a twining vine Tripterygium wilfordii. SJL/J mice were primed with PLP(139-151) peptide and orally treated with triptolide (100mug/kg per day) from the day of EAE induction (preventive regime) and after the onset of clinical signs (therapeutic regime). Triptolide delayed disease onset, reduced clinical symptoms, decreased the relapse rate, and suppressed inflammation and demyelination in CNS tissue of EAE mice when compared to vehicle-treated animals. Molecular analysis revealed a marked increase of heat shock protein 70 (Hsp70) mRNA and protein in the CNS tissue of triptolide-treated animals. Cytokine and chemokine expression analysis from EAE tissues and in vitro macrophages detected a decrease of key pro-inflammatory mRNAs. Triptolide inhibited IkappaBalpha phosphorylation and NF-kappaB nuclear translocation by stabilization of NF-kappaB/IkappaBalpha complex, possibly due to a direct physical interaction between NF-kappaB and Hsp70 proteins. Lymph node cell proliferation assay in EAE confirmed the immunosuppressive efficacy of triptolide. Our data indicate that daily oral administration of triptolide exhibits not only a preventive but also a therapeutic effect on EAE. These effects might be explained by the increase in Hsp70 levels driven by triptolide and stabilization of the NF-kappaB/IkappaBalpha complex leading to an attenuated inflammatory response.
Kizelsztein
Pablo
P
Biotech Center, SEBS, Rutgers University, 59 Dudley Road, New Brunswick, NJ 08901, USA. pablok@aesop.rutgers.edu
Komarnytsky
Slavko
S
Raskin
Ilya
I
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D002461:Cell Line, Transformed; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage* / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism*; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018991:Myelin Proteolipid Protein; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D008517:Phytotherapy / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D029757:Tripterygium / Q000737:chemistry; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D004224:Diterpenes; D004852:Epoxy Compounds; D018840:HSP70 Heat-Shock Proteins; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D018991:Myelin Proteolipid Protein; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D010446:Peptide Fragments; D010616:Phenanthrenes; D012333:RNA, Messenger; C435023:myelin proteolipid protein (139-151); D000072000:NF-KappaB Inhibitor alpha; C001899:triptolide