title: Potent anti-inflammatory activity of betulinic acid treatment in a model of lethal endotoxemia.
abstract: Betulinic acid (BA) is a lupane-type triterpene with a number of biological activities already reported. While potent anti-HIV and antitumoral activities were attributed to BA, it is considered to have a moderate anti-inflammatory activity. Here we evaluated the effects of BA in a mouse model of endotoxic shock. Endotoxemia was induced through intraperitoneally LPS administration, nitric oxide (NO) and cytokines were assessed by Griess method and ELISA, respectively. Treatment of BALB/c mice with BA at 67 mg/kg caused a 100% survival against a lethal dose of lipopolysaccharide (LPS). BA treatment caused a reduction in TNF-α production induced by LPS but did not alter IL-6 production. Moreover, BA treatment increased significantly the serum levels of IL-10 compared to vehicle-treated, LPS-challenged mice. To investigate the role of IL-10 in BA-induced protection, wild-type and IL-10(-/-) mice were studied. In contrast to the observations in IL-10(+/+) mice, BA did not protect IL-10(-/-) mice against a lethal LPS challenge. Addition of BA inhibited the production of pro-inflammatory mediators by macrophages stimulated with LPS, while promoting a significant increase in IL-10 production. BA-treated peritoneal exudate macrophages produced lower concentrations of TNF-α and NO and higher concentrations of IL-10 upon LPS stimulation. Similarly, macrophages obtained from BA-treated mice produced less pro-inflammatory mediators and increased IL-10 when compared to non-stimulated macrophages obtained from vehicle-treated mice. In conclusion, we have shown that BA has a potent anti-inflammatory activity in vivo, protecting mice against LPS by modulating TNF-α production by macrophages in vivo through a mechanism dependent on IL-10.
authors.affiliation: Laboratory of Tissue Engineering and Immunopharmacology Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Rua Waldemar Falcão, 121, 40296-750, Salvador, Bahia, Brazil.
authors.forename: José Fernando Oliveira
authors.initials: JF
authors.lastname: Costa
authors.affiliation: Laboratory of Pharmaceutical Technology, Federal University of Paraíba, João Pessoa, Cidade Universitária, s/n, 58051-900, João Pessoa, PB, Brazil.
authors.forename: José Maria
authors.initials: JM
authors.lastname: Barbosa-Filho
authors.affiliation: Laboratory of Pharmaceutical Technology, Federal University of Paraíba, João Pessoa, Cidade Universitária, s/n, 58051-900, João Pessoa, PB, Brazil.
authors.forename: Gabriela Lemos de Azevedo
authors.initials: GL
authors.lastname: Maia
authors.affiliation: Laboratory of Tissue Engineering and Immunopharmacology Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Rua Waldemar Falcão, 121, 40296-750, Salvador, Bahia, Brazil; Department of Life Sciences, State University of Bahia, Rua Silveira Martins, 2555, 41150-000, Salvador, BA, Brazil.
authors.forename: Elisalva Teixeira
authors.initials: ET
authors.lastname: Guimarães
authors.affiliation: Laboratory of Tissue Engineering and Immunopharmacology Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Rua Waldemar Falcão, 121, 40296-750, Salvador, Bahia, Brazil.
authors.forename: Cássio Santana
authors.initials: CS
authors.lastname: Meira
authors.affiliation: Laboratory of Tissue Engineering and Immunopharmacology Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Rua Waldemar Falcão, 121, 40296-750, Salvador, Bahia, Brazil; Center of Biotecnology and Cell Therapy, São Rafael Hospital, Av. São Rafael, 2152. São Marcos 41253-190, Salvador, BA, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribeiro-dos-Santos
authors.affiliation: Laboratory of Tissue Engineering and Immunopharmacology Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Rua Waldemar Falcão, 121, 40296-750, Salvador, Bahia, Brazil.
authors.forename: Lain Carlos Pontes
authors.initials: LC
authors.lastname: de Carvalho
authors.affiliation: Laboratory of Tissue Engineering and Immunopharmacology Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Rua Waldemar Falcão, 121, 40296-750, Salvador, Bahia, Brazil; Center of Biotecnology and Cell Therapy, São Rafael Hospital, Av. São Rafael, 2152. São Marcos 41253-190, Salvador, BA, Brazil. Electronic address: milena@bahia.fiocruz.br.
authors.forename: Milena Botelho Pereira
authors.initials: MB
authors.lastname: Soares
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy*; D005786:Gene Expression Regulation / Q000187:drug effects; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000008:administration & dosage / Q000627:therapeutic use*; D000094062:Betulinic Acid
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D016753:Interleukin-10; D009569:Nitric Oxide; D000094062:Betulinic Acid
keywords: Anti-inflammatory activity; Betulinic acid; Cytokines; Endotoxemia; Macrophages