title: Distinct responses of monocytes to Toll-like receptor ligands and inflammatory cytokines.
abstract: In this study we compared the activation of monocytes by different bacterial products via Toll-like receptors (TLR), and by different proinflammatory mediators. In response to TLR-2, -4 and -5 engagement, approximately 50% of monocytes produced TNF-alpha, compared to only 5% after induction with IFN-gamma or GM-CSF. Furthermore, a small proportion of monocytes produced IL-10 after stimulation via TLR, but not after stimulation with cytokines. Both TLR-ligands and inflammatory cytokines induced the expression of CD25, CD69, CD80 and, surprisingly, also of CD83, commonly regarded as an activation marker for mature dendritic cells (DC). Conversely, TLR-ligands downregulated CD38, CD86 and ICOS-L. Importantly, signaling lymphocytic activation molecule (SLAM; CD150) was identified as a monocyte activation marker that could be induced ex novo via TLR-2, -4 and -5, but not by single stimulation with monocyte activators like IL-1, TNF-alpha, IFN-beta, IFN-gamma, GM-CSF or CD40-L. SLAM expression was transient and required mitogen activated protein kinase (MAPK) p38, but not ERK or JNK, and was surprisingly independent of NF-kappaB. SLAM+ monocytes, which are absent in blood, were detected in spleen and tonsils, where they could be localized to T-cell areas and germinal centers. Together, by comparing the response of monocytes to TLR-ligands and inflammatory cytokines, we have identified a monocyte activation marker, SLAM, which differs in its inducibility from other monocyte activation markers. SLAM+ monocytes and macrophages were identified for the first time in vivo. Their presence might be a sign of innate immune activation.
authors.affiliation: Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, D-82152 Martinsried, Germany.
authors.forename: Cinthia
authors.initials: C
authors.lastname: Farina
authors.forename: Diethilde
authors.initials: D
authors.lastname: Theil
authors.forename: Barbara
authors.initials: B
authors.lastname: Semlinger
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
mesh_terms: D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology*; D006023:Glycoproteins / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D007136:Immunoglobulins / Q000032:analysis / Q000378:metabolism*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D014066:Palatine Tonsil / Q000166:cytology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013154:Spleen / Q000166:cytology; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D006023:Glycoproteins; D007136:Immunoglobulins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C000604059:SLAMF1 protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D048051:p38 Mitogen-Activated Protein Kinases