title: Sugar-Modified Poly(propylene imine) Dendrimers Stimulate the NF-κB Pathway in a Myeloid Cell Line.
abstract: Fourth-generation poly(propylene imine) dendrimers fully surface-modified by maltose (dense shell, PPI-m DS) were shown to be biocompatible in cellular models, which is important for their application in drug delivery. We decided to verify also their inherent bioactivity, including immunomodulatory activity, for potential clinical applications. We tested their effects on the THP-1 monocytic cell line model of innate immunity effectors.
  
  
  
  To estimate the cytotoxicity of dendrimers the reasazurin assay was performed. The expression level of NF-κB targets: IGFBP3, TNFAIP3 and TNF was determined by quantitative real-time RT-PCR. Measurement of NF-κB p65 translocation from cytoplasm to nucleus was conducted with a high-content screening platform and binding of NF-κB to a consensus DNA probe was determined by electrophoretic mobility shift assay. The cytokine assay was performed to measure protein concentration of TNFalpha and IL-4.
  
  
  
  We found that PPI-m DS did not impact THP-1 viability and growth even at high concentrations (up to 100 μM). They also did not induce expression of genes for important signaling pathways: Jak/STAT, Keap1/Nrf2 and ER stress. However, high concentrations of 4th generation PPI-m DS (25-100 μM), but not their 3rd generation counterparts, induced nuclear translocation of p65 NF-κB protein and its DNA-binding activity, leading to NF-κB-dependent increased expression of mRNA for NF-κB targets: IGFBP3, TNFAIP3 and TNF. However, no increase in pro-inflammatory cytokine secretion was detected.
  
  
  
  We conclude that maltose-modified PPI dendrimers of specific size could exert a modest immunomodulatory effect, which may be advantageous in clinical applications (e.g. adjuvant effect in anti-cancer vaccines).
authors.affiliation: Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236, Lodz, Poland. ijatczak@biol.uni.lodz.pl.
authors.forename: Izabela
authors.initials: I
authors.lastname: Jatczak-Pawlik
authors.affiliation: Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236, Lodz, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Gorzkiewicz
authors.affiliation: Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236, Lodz, Poland.|Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236, Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Studzian
authors.affiliation: Leibniz Institute of Polymer Research Dresden, Hohe Str. 6, 01069, Dresden, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Appelhans
authors.affiliation: Leibniz Institute of Polymer Research Dresden, Hohe Str. 6, 01069, Dresden, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Voit
authors.affiliation: Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236, Lodz, Poland.|Laboratory of Transcriptional Regulation, Institute of Medical Biology PAS, 106 Lodowa St., 93-232, Lodz, Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Pulaski
authors.affiliation: Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska St., 90-236, Lodz, Poland.|Leibniz Institute of Polymer Research Dresden, Hohe Str. 6, 01069, Dresden, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klajnert-Maculewicz
mesh_terms: D002460:Cell Line; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008320:Maltose / Q000737:chemistry / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology*; D011126:Polypropylenes / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D012333:RNA, Messenger / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D000073893:Sugars / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology
chemical_list: D050091:Dendrimers; D016328:NF-kappa B; D011126:Polypropylenes; D012333:RNA, Messenger; D000073893:Sugars; D051996:Transcription Factor RelA; C443641:poly(propyleneimine); D015847:Interleukin-4; D008320:Maltose
keywords: NF-κB; PPI dendrimers; glycodendrimers; immunomodulation; monocytes