title: Prebiotic oligosaccharides directly modulate proinflammatory cytokine production in monocytes via activation of TLR4.
abstract: METHODS
  Prebiotic oligosaccharides are currently used in a variety of clinical settings for their effects on intestinal microbiota. Here, we have examined the direct, microbiota independent, effects of prebiotics on monocytes and T lymphocytes in vitro.
  
  
  RESULTS
  Prebiotics generally evoked cytokine secretion (TNF-α, IL-6, and IL-10) by mouse splenocytes but inhibited LPS -induced IFN-γ and IL-17 release. Inulin was found to enhance LPS-induced IL-10 secretion. Splenocytes from TLR4(-/-) (where TLR is Toll-like receptor) mice showed a markedly depressed response. Conversely, in both basal and LPS-stimulated conditions, prebiotic inhibition of IFN-γ levels was preserved. These results suggested a predominant effect on monocytes via TLR4 ligation and possible inhibition of T cells. Hence, we studied the modulation of primary rat monocytes and T lymphocytes, focusing on fructooligosaccharides (FOS) and inulin. In monocytes, FOS and inulin induced TNF-α, growth-regulated oncogene α, and IL-10, but not IL-1β release. The NF-κB inhibitor Bay 11-7082 fully prevented these effects. Pharmacological evidence also indicated a significant involvement of mitogen-activated protein kinase and phosphatidylinositol-3-kinase. There was little effect on T cells. FOS and inulin also generally increased TNF-α, IL-1β, and IL-10, but not IL-8, in human peripheral blood monocytes.
  
  
  CONCLUSIONS
  We conclude that prebiotics may act as TLR4 ligands or as indirect TLR4 modulators to upregulate cytokine secretion in monocytes.
authors.affiliation: Department of Biochemistry and Molecular Biology II, CIBERehd, School of Pharmacy, University of Granada, Granada, Spain.
authors.forename: Fermín
authors.initials: F
authors.lastname: Capitán-Cañadas
authors.forename: Mercedes
authors.initials: M
authors.lastname: Ortega-González
authors.forename: Emilia
authors.initials: E
authors.lastname: Guadix
authors.forename: Antonio
authors.initials: A
authors.lastname: Zarzuelo
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Suárez
authors.forename: Fermín Sánchez
authors.initials: FS
authors.lastname: de Medina
authors.forename: Olga
authors.initials: O
authors.lastname: Martínez-Augustin
mesh_terms: D000328:Adult; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007444:Inulin / Q000008:administration & dosage*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009844:Oligosaccharides / Q000008:administration & dosage*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D056692:Prebiotics; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009570:Nitriles; D009844:Oligosaccharides; D056692:Prebiotics; D013450:Sulfones; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C116580:fructooligosaccharide; D016753:Interleukin-10; D007371:Interferon-gamma; D007444:Inulin; D058539:Phosphatidylinositol 3-Kinase; D020928:Mitogen-Activated Protein Kinases
keywords: Fructooligosaccharides; Inulin; Monocyte; NF-κB; Toll like receptor 4