title: Beta-defensins activate macrophages and synergize in pro-inflammatory cytokine expression induced by TLR ligands.
abstract: Our previous studies indicated that mouse beta defensin 14 (mBD14, Defb14), a newly identified member of the beta-defensin super family, interacts with the chemokine receptors CCR2 and CCR6. In this study we report that pre-stimulation of primary mouse macrophages with mBD14 results in a synergistic, enhanced expression of pro-inflammatory cytokines and chemokines induced by TLR ligand re-stimulation. Experiments using specific inhibitors of G(i)-protein-coupled receptor signaling provide evidence that this effect seems to be mediated by a G(i)-protein-coupled receptor expressed on bone marrow derived macrophages. However, using primary macrophages derived from CCR6- and CCR2-deficient mice clearly demonstrated that the enhanced pro-inflammatory cytokine and chemokine expression is independent of the chemokine receptors CCR6 and CCR2. Additionally, signaling pathway analysis indicated that mBD14 is capable of inducing MAPK ERK1/2 phosphorylation and the induction of CD86 and F4/80 expression in bone marrow-derived macrophages after mBD14 stimulation. Collectively, our data indicate that β-defensins activate primary macrophages and enhance pro-inflammatory responses by using G(i)PCRs in order to support inflammatory reactions induced by TLR ligands.
authors: Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors: Nicola
authors: N
authors: Barabas
authors: Johann
authors: J
authors: Röhrl
authors: Ernst
authors: E
authors: Holler
authors: Thomas
authors: T
authors: Hehlgans
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D004357:Drug Synergism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D061251:Primary Cell Culture; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D054399:Receptors, CCR6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D023083:beta-Defensins / Q000494:pharmacology*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; C498126:CCR6 protein, mouse; C515335:Ccr2 protein, mouse; C497965:Cd86 protein, mouse; D016207:Cytokines; D008070:Lipopolysaccharides; D054390:Receptors, CCR2; D054399:Receptors, CCR6; D011994:Recombinant Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D023083:beta-Defensins; C556378:beta-defensin-14, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3