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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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]
Total Authors: 8
Affiliation:
[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
Total Affiliations: 4
Document type: Journal article
Source: International Immunopharmacology; v. 58, p. 160-165, MAY 2018.
Web of Science Citations: 1
Abstract

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)

FAPESP's process: 12/22048-2 - Investigation into the pro-inflammatory properties of TNF-alpha and heme in leukocytes in vitro and in vivo.
Grantee:Angélica Aparecida Antoniellis Silveira
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 14/19173-5 - Vascular inflammation: pathophysiological mechanisms of induction and pathways of cellular activation
Grantee:Nicola Amanda Conran Zorzetto
Support type: Regular Research Grants
FAPESP's process: 10/19916-7 - Evaluation on elastic fiber synthesis in cell culture obtained from fibrillin-1 defficient mice: Losartan's effect studies
Grantee:Claudio Chrysostomo Werneck
Support type: Regular Research Grants