Attenuation of TNF-induced neutrophil adhesion by simvastatin is associated with the inhibition of Rho-GTPase activity, p50 activity and morphological changes

Autor(es)

Antoniellis Silveira, Angelica Aparecida ^[1] ; Dominical, Venina Marcela ^{[1, 2]} ; Vital, Daiana Morelli ^[1] ; Ferreira, Jr., Wilson Alves ^[1] ; Maranhao Costa, Fabio Trindade ^[3] ; Werneck, Claudio C. ^[4] ; Costa, Fernando Ferreira ^[1] ; Conran, Nicola ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, UNICAMP, Sch Med, Hematol & Hemotherapy Ctr, Campinas, SP - Brazil

^[2] NHLBI, Flow Cytometry Core Facil, NIH, Bldg 10, Bethesda, MD 20892 - USA

^[3] Univ Estadual Campinas, UNICAMP, Inst Biol, Lab Trop Dis Prof Dr Luiz Jacintho da Silva, Dept, Campinas, SP - Brazil

^[4] Univ Estadual Campinas, UNICAMP, Inst Biol, Dept Biochem & Tissue Biol, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: International Immunopharmacology; v. 58, p. 160-165, MAY 2018.
• Citações Web of Science: 1

Resumo

Neutrophil adhesion to the vasculature in response to potent inflammatory stimuli, such as TNF-alpha (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 beta(2)-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 (beta(2)-integrin activity. Additionally, TNF augmented the activity of the p50 NF kappa B subunit in human neutrophils and TNF-induced neutrophil adhesion and beta(2)-integrin activity could be abolished using pharmacological inhibitors of NF kappa B 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, NF kappa B translocation and, consequently, beta(2)-integrin activity. (AU)

• Processo FAPESP: 12/22048-2 - Investigação das propriedades pro-inflamatórias do TNF-alfa e do heme em leucócitos in vitro e in vivo.
• Beneficiário: Angélica Aparecida Antoniellis Silveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/19916-7 - Avaliação da síntese de fibras elásticas em cultura de células obtidas de camundongos deficientes em fibrilina-1: estudo do efeito do Losartan
• Beneficiário: Claudio Chrysostomo Werneck
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/19173-5 - Inflamação vascular: mecanismos fisiopatológicos de indução e vias de ativação celular
• Beneficiário: Nicola Amanda Conran Zorzetto
• Modalidade de apoio: Auxílio à Pesquisa - Regular