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Attenuation of TNF-induced neutrophil adhesion by simvastatin is associated with the inhibition of Rho-GTPase activity, p50 activity and morphological changes.
Antoniellis Silveira, Angélica Aparecida; Dominical, Venina Marcela; Morelli Vital, Daiana; Alves Ferreira, Wilson; Trindade Maranhão Costa, Fabio; Werneck, Claudio C; Ferreira Costa, Fernando; Conran, Nicola.
Afiliação
  • Antoniellis Silveira AA; Hematology and Hemotherapy Center, School of Medicine, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil.
  • Dominical VM; Hematology and Hemotherapy Center, School of Medicine, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil.
  • Morelli Vital D; Hematology and Hemotherapy Center, School of Medicine, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil.
  • Alves Ferreira W; Hematology and Hemotherapy Center, School of Medicine, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil.
  • Trindade Maranhão Costa F; Laboratory of Tropical Diseases - Prof. Dr. Luiz Jacintho da Silva, Department of Genetics, Evolution and Bioagents, Institute of Biology (IB), University of Campinas-UNICAMP, Brazil.
  • Werneck CC; Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, Brazil.
  • Ferreira Costa F; Hematology and Hemotherapy Center, School of Medicine, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil.
  • Conran N; Hematology and Hemotherapy Center, School of Medicine, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil. Electronic address: conran@unicamp.br.
Int Immunopharmacol ; 58: 160-165, 2018 May.
Article em En | MEDLINE | ID: mdl-29604489
Neutrophil adhesion to the vasculature in response to potent inflammatory stimuli, such as TNF-α (TNF), can contribute to atheroprogression amongst other pathophysiological mechanisms. Previous studies have shown that simvastatin, a statin with known pleiotropic anti-inflammatory properties, can partially abrogate the effects of TNF-induced neutrophil adhesion, in association with the modulation of ß2-integrin expression. We aimed to further characterize the effects of this statin on neutrophil and leukocyte adhesive mechanisms in vitro and in vivo. A microfluidic assay confirmed the ability of simvastatin to inhibit TNF-induced human neutrophil adhesion to fibronectin ligand under conditions of shear stress, while intravital imaging microscopy demonstrated an abrogation of leukocyte recruitment by simvastatin in the microvasculature of mice that had received a TNF stimulus. This inhibition of neutrophil adhesion was accompanied by the inhibition of TNF-induced RhoA activity in human neutrophils, and alterations in cell morphology and ß2-integrin activity. Additionally, TNF augmented the activity of the p50 NFκB subunit in human neutrophils and TNF-induced neutrophil adhesion and ß2-integrin activity could be abolished using pharmacological inhibitors of NFκB translocation, BAY11-7082 and SC514. Accordingly, the TNF-induced elevation of neutrophil p50 activity was abolished by simvastatin. In conclusion, our data provide further evidence of the ability of simvastatin to inhibit neutrophil adhesive interactions in response to inflammatory stimuli, both in vivo and in vitro. Simvastatin appears to inhibit neutrophil adhesion by interfering in TNF-induced cytoskeletal rearrangements, in association with the inhibition of Rho A activity, NFκB translocation and, consequently, ß2-integrin activity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Hidroximetilglutaril-CoA Redutases / Sinvastatina / Proteínas rho de Ligação ao GTP / Subunidade p50 de NF-kappa B / Neutrófilos Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Int Immunopharmacol Assunto da revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda
Texto completo
Adicionar na Minha BVS
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XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Hidroximetilglutaril-CoA Redutases / Sinvastatina / Proteínas rho de Ligação ao GTP / Subunidade p50 de NF-kappa B / Neutrófilos Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Int Immunopharmacol Assunto da revista: ALERGIA E IMUNOLOGIA / FARMACOLOGIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda