Involvement of suppressors of cytokine signaling in toll-like receptor-mediated block of dendritic cell differentiation.
Dendritic cells (DCs) are important sentinels within innate immunity, monitoring the presence of infectious microorganisms. They operate in 2 different maturation stages, with transition from immature to mature DCs being induced by activation of toll-like receptors (TLRs). However, TLRs are also expressed on precursor cells of DCs. Here we analyzed the effects of TLR stimulation during the process of granulocyte-macrophage-colony-stimulating factor (GM-CSF)-mediated in vitro generation of immature DCs from precursor cells. We show that TLR triggering deviated phenotypic and functional differentiation from CD14+ monocytes to CD1a+ DCs. Similar results were obtained when differentiation of murine myeloid DCs from bone marrow cells was analyzed. The inhibitory effects were independent of soluble factors. TLR stimulation in DC precursor cells induced proteins of the suppressor of cytokine signaling family (SOCS), which correlated with loss of sensitivity to GM-CSF. Overexpression of SOCS-1 abolished GM-CSF signal transduction. Moreover, forced SOCS-1 expression in DC precursors mimicked the inhibitory effects on DC generation observed for TLR stimulation. The results indicate that TLR stimulation during the period of DC generation interferes with and deviates DC differentiation and that these effects are mediated particularly by SOCS-1.
Bartz
Holger
H
Department of Medical Microbiology and Hygiene, Hygiene Institute, University of Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany. holger.bartz@med.uni-heidelberg.de
Avalos
Nicole M
NM
Baetz
Andrea
A
Heeg
Klaus
K
Dalpke
Alexander H
AH
D000818:Animals; D018949:Antigens, CD1 / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000494:pharmacology; D007113:Immunity, Innate / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology*; D051193:Toll-Like Receptors / Q000172:deficiency / Q000276:immunology*
D018949:Antigens, CD1; C419393:CD1a antigen; D018950:Lipopolysaccharide Receptors; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051193:Toll-Like Receptors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor