title: Interleukin-18 secretion and Th1-like cytokine responses in human peripheral blood mononuclear cells under the influence of the toll-like receptor-5 ligand flagellin.
abstract: Flagellin is the major protein component of the flagella from motile bacteria and was identified as the ligand for toll-like receptor (TLR)-5. Whereas its effects on epithelial cells have been studied in detail, activation of human peripheral blood mononuclear cells (PBMC) by flagellin is characterized only partially. By using the recombinant protein of Salmonella muenchen we confirm the proinflammatory nature of flagellin as detected by nuclear factor-kappaB activation and interleukin (IL)-8 production. Aim of the current study was to elucidate in PBMC effects of flagellin on IL-18 and Th1-like cytokine responses. We report that flagellin in pathophysiologically relevant concentrations augmented release of mature IL-18 by THP-1 monocytes, PBMC, and whole blood stimulated with nigericin or by ATP-mediated P2X7 purinergic receptor activation. Further key functions of the IL-18/IL-12/interferon-gamma (IFNgamma) pathway were upregulated by flagellin. Flagellin synergized with IL-12 for production of IFN-gamma and augmented secretion of interferon-inducible protein-10, a CXC-chemokine that is key to the generation of Th1-type responses. In contrast, neither IL-18-binding protein nor IL-4 was affected. Taken together, the present data demonstrate for the first time that flagellin at concentrations that are detectable in the blood compartment during sepsis efficiently enhances the IL-18/IL-12/IFNgamma pathway and thus Th1-like cytokine responses in PBMC.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Bachmann
authors.forename: Katharina
authors.initials: K
authors.lastname: Horn
authors.forename: Marco A
authors.initials: MA
authors.lastname: Poleganov
authors.forename: Jens
authors.initials: J
authors.lastname: Paulukat
authors.forename: Marcel
authors.initials: M
authors.lastname: Nold
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Heiko
authors.initials: H
authors.lastname: Mühl
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000378:metabolism; D005408:Flagellin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D016328:NF-kappa B / Q000378:metabolism; D009550:Nigericin / Q000494:pharmacology; D058910:Purinergic P2 Receptor Agonists; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins / Q000494:pharmacology; D012475:Salmonella / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D020382:Interleukin-18; D008024:Ligands; D016328:NF-kappa B; C546468:P2RX7 protein, human; D058910:Purinergic P2 Receptor Agonists; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins; D051198:Toll-Like Receptor 5; D005408:Flagellin; D018664:Interleukin-12; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D009550:Nigericin