18 Beta-glycyrrhetinic acid triggers curative Th1 response and nitric oxide up-regulation in experimental visceral leishmaniasis associated with the activation of NF-kappa B.
The efficacy of 18beta-glycyrrhetinic acid (GRA), a pentacyclic triterpene belonging to the beta-amyrin series of plant origin, was evaluated in experimental visceral leishmaniasis. GRA is reported to have antitumor and immunoregulatory activities, which may be attributable in part to the induction of NO. Indeed, an 11-fold increase in NO production was observed with 20 microM GRA in mouse peritoneal macrophages infected with Leishmania donovani promastigotes. In addition to having appreciable inhibitory effects on amastigote multiplication within macrophages (IC(50), 4.6 microg/ml), complete elimination of liver and spleen parasite burden was achieved by GRA at a dose of 50 mg/kg/day, given three times, 5 days apart, in a 45-day mouse model of visceral leishmaniasis. GRA treatment resulted in reduced levels of IL-10 and IL-4, but increased levels of IL-12, IFN-gamma, TNF-alpha, and inducible NO synthase, reflecting a switch of CD4(+) differentiation from Th2 to Th1. This treatment is likely to activate immunity, thereby imparting resistance to reinfection. GRA induced NF-kappaB migration into the nucleus of parasite-infected cells and caused a diminishing presence of IkappaB in the cytoplasm. The lower level of cytoplasmic IkappaBalpha in GRA-treated cells resulted from increased phosphorylation of IkappaBalpha and higher activity of IkappaB kinase (IKK). Additional experiments demonstrated that GRA does not directly affect IKK activity. These results suggest that GRA exerts its effects at some level upstream of IKK in the signaling pathway and induces the production of proinflammatory mediators through a mechanism that, at least in part, involves induction of NF-kappaB activation.
Molecular Cell Biology Laboratory, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Calcutta 700032, India.
Anindita
A
Ukil
Aruna
A
Biswas
Tapasi
T
Das
Pijush K
PK
Das
D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D007893:Leishmania donovani / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051996:Transcription Factor RelA; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
D000981:Antiprotozoal Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D006034:Glycyrrhetinic Acid