title: Resveratrol as a natural anti-tumor necrosis factor-α molecule: implications to dendritic cells and their crosstalk with mesenchymal stromal cells.
abstract: Dendritic cells (DC) are promising targets for inducing tolerance in inflammatory conditions. Thus, this study aims to investigate the effects of the natural anti-inflammatory molecule resveratrol on human DC at phenotypic and functional levels, including their capacity to recruit mesenchymal stem/stromal cells (MSC). Primary human monocyte-derived DC and bone marrow MSC were used. DC immunophenotyping revealed that small doses of resveratrol (10 µM) reduce cell activation in response to tumor necrosis factor (TNF)-α, significantly decreasing surface expression of CD83 and CD86. Functionally, IL-12/IL-23 secretion induced by TNF-α was significantly reduced by resveratrol, while IL-10 levels increased. Resveratrol also inhibited T cell proliferation, in response to TNF-α-stimulated DC. The underlying mechanism was investigated by Western blot and imaging flow cytometry (ImageStreamX), and likely involves impairment of nuclear translocation of the p65 NF-κB subunit. Importantly, results obtained demonstrate that DC are able to recruit MSC through extracellular matrix components, and that TNF-α impairs DC-mediated recruitment. Matrix metalloproteinases (MMP) produced by both cell populations were visualized by gelatin zymography. Finally, time-lapse microscopy analysis revealed a significant decrease on DC and MSC motility in co-cultures, indicating cell interaction, and TNF-α further decreased MSC motility, while resveratrol recovered it. Thus, the current study points out the potential of resveratrol as a natural anti-TNF-α drug, capable of modulating DC phenotype and function, as well as DC-mediated MSC recruitment.
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; Faculdade de Engenharia, Universidade do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
authors.forename: Andreia M
authors.initials: AM
authors.lastname: Silva
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
authors.forename: Marta I
authors.initials: MI
authors.lastname: Oliveira
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
authors.forename: Laura
authors.initials: L
authors.lastname: Sette
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Almeida
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; Faculdade de Ciências, Universidade do Porto, Porto, Portugal; Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Oliveira
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
authors.forename: Mário A
authors.initials: MA
authors.lastname: Barbosa
authors.affiliation: INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
authors.forename: Susana G
authors.initials: SG
authors.lastname: Santos
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D021381:Protein Transport / Q000187:drug effects; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D000077185:Resveratrol