curative effect of 18β-glycyrrhetinic acid in experimental visceral leishmaniasis depends on phosphatase-dependent modulation of cellular map kinases18β-glycyrrhetinic酸实验内脏利什曼病的疗效取决于phosphatase-dependent调制的细胞激酶地图.pdfVIP

Curative Effect of 18b-Glycyrrhetinic Acid in Experimental Visceral Leishmaniasis Depends on Phosphatase-Dependent Modulation of Cellular MAP Kinases 1. 2. 2 1 2 Anindita Ukil , Susanta Kar , Supriya Srivastav , Kuntal Ghosh , Pijush K. Das * 1 Department of Biochemistry, Calcutta University, Kolkata, India, 2 Molecular Cell Biology Laboratory, Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, India Abstract We earlier showed that 18b-glycyrrhetinic acid (GRA), a pentacyclic triterpenoid from licorice root, could completely cure visceral leishmaniasis in BALB/c mouse model. This was associated with induction of nitric oxide and proinflammatory cytokine production through the up regulation of NF-kB. In the present study we tried to decipher the underlying cellular mechanisms of the curative effect of GRA. Analysis of MAP kinase pathways revealed that GRA caused strong activation of p38 and to a lesser extent, ERK in bone marrow-derived macrophages (BMDM). Almost complete abrogation of GRA- induced cytokine production in presence of specific inhibitors of p38 and ERK1/2 confirmed the involvement of these MAP kinases in GRA-mediated responses. GRA induced mitogen- and stress-activated protein kinase (MSK1) activity in a time- dependent manner suggested that GRA-mediated NF-kB transactivation is mediated by p38, ERK and MSK1 pathway. As kinase/phosphatase balance plays an important role in modulating infection, the effect of GRA on MAPK directed phosphatases (MKP) was studied. GRA markedly reduced the expression and activities of three phosphatases, MKP1, MKP3 and protein phosphatase 2A (PP2A) along with a substantial reduction of p38 and