title: Immune modulation by different types of β2→1-fructans is toll-like receptor dependent.
abstract: BACKGROUND
  β2→1-fructans are dietary fibers. Main objectives of this study were 1) to demonstrate direct signalling of β2→1-fructans on immune cells, 2) to study whether this is mediated by the pattern recognition receptors Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain-containing proteins (NODs), and 3) to relate the observed effects to the chain length differences in β2→1-fructans.
  
  
  METHODS
  Four different β2→1-fructan formulations were characterised for their chain length profile. Human peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with β2→1-fructans, and production of IL-1Ra, IL-1β, IL-6, IL-10, IL-12p70, and TNF-α was analysed. Reporter cells for TLRs and NODs were incubated with β2→1-fructans and analysed for NF-κB/AP-1 activation.
  
  
  RESULTS
  Cytokine production in human PBMCs was dose- and chain length-dependent. Strikingly, short chain enriched β2→1-fructans induced a regulatory cytokine balance compared to long chain enriched β2→1-fructans as measured by IL-10/IL-12 ratios. Activation of reporter cells showed that signalling was highly dependent on TLRs and their adapter, myeloid differentiation primary response protein 88 (MyD88). In human embryonic kidney reporter cells, TLR2 was prominently activated, while TLR4, 5, 7, 8, and NOD2 were mildly activated.
  
  
  CONCLUSIONS
  β2→1-fructans possess direct signalling capacity on human immune cells. By activating primarily TLR2, and to a lesser extent TLR4, 5, 7, 8, and NOD2, β2→1-fructan stimulation results in NF-κB/AP-1 activation. Chain length of β2→1-fructans is important for the induced activation pattern and IL-10/IL-12 ratios.
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. L.M.Vogt@umcg.nl
authors.forename: Leonie
authors.initials: L
authors.lastname: Vogt
authors.forename: Uttara
authors.initials: U
authors.lastname: Ramasamy
authors.forename: Diederick
authors.initials: D
authors.lastname: Meyer
authors.forename: Gerdie
authors.initials: G
authors.lastname: Pullens
authors.forename: Koen
authors.initials: K
authors.lastname: Venema
authors.forename: Marijke M
authors.initials: MM
authors.lastname: Faas
authors.forename: Henk A
authors.initials: HA
authors.lastname: Schols
authors.forename: Paul
authors.initials: P
authors.lastname: de Vos
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004043:Dietary Fiber / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005630:Fructans / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007444:Inulin / Q000737:chemistry / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D004043:Dietary Fiber; D005630:Fructans; D007155:Immunologic Factors; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; D007444:Inulin