title: Human beta-defensin-2 and -3 enhance pro-inflammatory cytokine expression induced by TLR ligands via ATP-release in a P2X7R dependent manner.
abstract: Our previous results indicate that HBD2 and HBD3 are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner. In this study we report that pre-stimulation of primary human macrophages or THP-1 cells with HBD2 or HBD3 results in a synergistic, enhanced expression of pro-inflammatory cytokines and chemokines induced by TLR ligand re-stimulation. Experiments using specific inhibitors of the ATP-gated channel receptor P2X7 or its functional ligand ATP, suggest that the enhanced expression of pro-inflammatory cytokines and chemokines seems to be mediated by P2X7R. Furthermore, our data provide evidence that beta-defensins do not directly interact with P2X7R but rather induce the release of intracellular ATP. Interference with ATP release abrogated the synergistic effect mediated by HBD2 and HBD3 pre-stimulation in THP-1 cells. However, extracellular ATP alone seems not to be sufficient to elicit the enhanced synergistic effect on cytokine and chemokine expression observed by pre-stimulation of primary human macrophages or THP-1 cells with HBD2 or HBD3. Collectively, our findings provide new insights into the molecular mechanisms how HBD2 and HBD3 interact with cells of myeloid origin and demonstrate their immuno-modulating functions during innate immune responses.
authors.affiliation: Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wanke
authors.affiliation: Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Mauch-Mücke
authors.affiliation: Department of Internal Medicine III, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Holler
authors.affiliation: Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany. Electronic address: Thomas.hehlgans@klinik.uni-regensburg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hehlgans
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D015415:Biomarkers; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation; D018836:Inflammation Mediators / Q000378:metabolism*; D008024:Ligands; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*; D023083:beta-Defensins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016207:Cytokines; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D018836:Inflammation Mediators; D008024:Ligands; D058486:Receptors, Purinergic P2X7; D051193:Toll-Like Receptors; D023083:beta-Defensins; D000255:Adenosine Triphosphate
keywords: Beta-defensins; Pro-inflammatory cytokines; TLR agonists; p2x7 receptor