Submitted March 10, 2006
Accepted July 28, 2006
Involvement of suppressors of cytokine signaling in toll-like receptor-mediated block of dendritic cell differentiation
Holger Bartz*, Nicole M Avalos, Andrea Baetz, Klaus Heeg, and Alexander H Dalpke
Department of Medical Microbiology and Hygiene, University of Heidelberg, Germany
* Corresponding author; email: holger.bartz{at}med.uni-heidelberg.de.
Dendritic cells (DCs) are important sentinels within innate immunity monitoring the presence of infectious microorganisms. They operate in two 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. Over-expression 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.
