title: LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells.
abstract: Although promising for graft-versus-host disease (GvHD) treatment, MSC therapy still faces important challenges. For instance, increasing MSC migratory capacity as well as potentializing immune response suppression are of interest. For GvHD management, preventing opportunistic infections is also a valuable strategy, since immunocompromised patients are easy targets for infections. LL-37 is a host defense peptide (HDP) that has been deeply investigated due to its immunomodulatory function. In this scenario, the combination of MSC and LL-37 may result in a robust combination to be clinically used.
  
  
  
  In the present study, the effects of LL-37 upon the proliferation and migratory capacity of human placenta-derived MSCs (pMSCs) were assessed by MTT and wound scratch assays. The influence of LL-37 over the immunosuppressive function of pMSCs was then investigated using CFSE cell division kit. Flow cytometry and real-time PCR were used to investigate the molecular mechanisms involved in the effects observed.
  
  
  
  LL-37 had no detrimental effects over MSC proliferation and viability, as assessed by MTT assay. Moreover, the peptide promoted increased migratory behavior of pMSCs and enhanced their immunomodulatory function over activated human PBMCs. Strikingly, our data shows that LL-37 treatment leads to increased TLR3 levels, as shown by flow cytometry, and to an increased expression of factors classically related to immunosuppression, namely IDO, IL-10, TGF-β, IL-6, and IL-1β.
  
  
  
  Taken together, our observations may serve as groundwork for the development of new therapeutic strategies based on the combined use of LL-37 and MSCs, which may provide patients not only with an enhanced immunosuppression regime, but also with an agent to prevent opportunistic infections.
authors.affiliation: Laboratório de Farmacologia Molecular, Departamento de Ciências da Saúde, Universidade de Brasília, Campus Darcy Ribeiro, Brasília, DF, Brazil.
authors.forename: Martha
authors.initials: M
authors.lastname: Oliveira-Bravo
authors.affiliation: Laboratório de Hematologia, Departamento de Clínica Médica, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Bruno Braga
authors.initials: BB
authors.lastname: Sangiorgi
authors.affiliation: Laboratório de Hematologia, Departamento de Clínica Médica, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Josiane Lilian Dos Santos
authors.initials: JL
authors.lastname: Schiavinato
authors.affiliation: Laboratório de Análises Proteômicas e Bioquímicas, Centro de Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil.
authors.forename: Juliana Lott
authors.initials: JL
authors.lastname: Carvalho
authors.affiliation: Laboratório de Hematologia, Departamento de Clínica Médica, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Dimas Tadeu
authors.initials: DT
authors.lastname: Covas
authors.affiliation: Laboratório de Hematologia, Departamento de Clínica Médica, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Rodrigo Alexandre
authors.initials: RA
authors.lastname: Panepucci
authors.affiliation: Laboratório de Farmacologia Molecular, Departamento de Ciências da Saúde, Universidade de Brasília, Campus Darcy Ribeiro, Brasília, DF, Brazil.|S-Inova Biotech, Pós-graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil.
authors.forename: Francisco de Assis Rocha
authors.initials: FA
authors.lastname: Neves
authors.affiliation: Laboratório de Análises Proteômicas e Bioquímicas, Centro de Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil.
authors.forename: Octávio Luiz
authors.initials: OL
authors.lastname: Franco
authors.affiliation: Laboratório de Análises Proteômicas e Bioquímicas, Centro de Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, Brazil.
authors.forename: Rinaldo Wellerson
authors.initials: RW
authors.lastname: Pereira
authors.affiliation: Laboratório de Farmacologia Molecular, Departamento de Ciências da Saúde, Universidade de Brasília, Campus Darcy Ribeiro, Brasília, DF, Brazil. felipearaujo@unb.br.
authors.forename: Felipe
authors.initials: F
authors.lastname: Saldanha-Araujo
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010920:Placenta / Q000187:drug effects*; D011247:Pregnancy; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053583:Interleukin-1beta; D015850:Interleukin-6; D051196:Toll-Like Receptor 3; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D054804:Cathelicidins
keywords: GvHD; LL-37; Mesenchymal stromal cells; TLR