title: TLR mediated GSK3β activation suppresses CREB mediated IL-10 production to induce a protective immune response against murine visceral leishmaniasis.
abstract: During Leishmania donovani (LD) infection Interleukin (IL)-10 favors parasite replication and plays a central role as a target for immune-based therapy. Glycogen synthase kinase 3 (GSK3)β differentially regulates TLR-mediated cytokine production. CREB, an important transcription factor that induces IL-10 production is negatively regulated by GSK3β. However, down regulation of IL-10 via CREB suppression has not been well explored in controlling LD infection. Here we demonstrate that, the TLR4 agonist 29 KDa β 1,4-galactose terminal glycoprotein (GP29) of LD activated GSK3β through TLR4 to induce IL-12-mediated Nitric oxide (NO) production that resulted in effective parasite clearance from macrophages. GSK3β activation abrogated both CREB phosphorylation and IL-10 production. Two subcutaneous injections of GP29 at fortnightly intervals in a 4-week infected mouse model of LD resulted in a dominant IL-12-mediated NO production and 100% animals were protected against a subsequent challenge with virulent LD parasites. Complete absence of GP29 mediated protection with down regulated NO and IL-12 production and dominant IL-10 production in presence of the GSK3β inhibitor, Lithium chloride reiterated the role of GSK3β in disease resolution in the murine model of visceral leishmaniasis.
authors.affiliation: Division of Infectious Disease and Immunology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
authors.forename: Joydeep
authors.initials: J
authors.lastname: Paul
authors.affiliation: Division of Infectious Disease and Immunology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
authors.forename: Kshudiram
authors.initials: K
authors.lastname: Naskar
authors.affiliation: Division of Infectious Disease and Immunology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India.
authors.forename: Sayan
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Department of Biochemistry and Biophysics, University of Kalyani, Kalyani 741235, West Bengal, India.
authors.forename: Tapati
authors.initials: T
authors.lastname: Chakraborti
authors.affiliation: Division of Infectious Disease and Immunology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India; Department of Biochemistry and Biophysics, University of Kalyani, Kalyani 741235, West Bengal, India. Electronic address: tripti.de@hotmail.com.
authors.forename: Tripti
authors.initials: T
authors.lastname: De
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D006790:Host-Parasite Interactions / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism; D007893:Leishmania donovani / Q000737:chemistry / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000276:immunology* / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009569:Nitric Oxide / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D006023:Glycoproteins; C556062:IL10 protein, mouse; D015800:Protozoan Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D018664:Interleukin-12; D009569:Nitric Oxide; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Galactose terminal glycoprotein; Glycogen synthase kinase 3; Nitric oxide; Toll-like receptor; cAMP response element-binding protein