title: Suppressor of cytokine signaling 2 is a feedback inhibitor of TLR-induced activation in human monocyte-derived dendritic cells.
abstract: Dendritic cells (DCs) are key players in initiating and directing the immune response. Therefore, their activation state and functional differentiation need to be tightly controlled. The activating stimuli and their signaling networks have long been an area of focus in DC research. Recent investigations have also shed light on the mechanisms of counterregulation and fine-tuning of DC functions. One class of proteins involved in these processes is the family of suppressors of cytokine signaling (SOCS), whose members were originally described as feedback inhibitors of cytokine-induced JAK/STAT signaling. Essential roles in DC function have been assigned to SOCS1 and SOCS3. In this article, we show that SOCS2 also is involved in DC regulation. In human and in murine DCs, SOCS2 is a highly TLR-responsive gene, which is expressed in a time-delayed fashion beginning 8 h after TLR ligation. Functionally, silencing of SOCS2 in DCs results in hyperphosphorylation of STAT3 at later time points. As a consequence, SOCS2-deficient DCs secrete increased amounts of the cytokines IL-1β and IL-10, both being transcriptional targets of STAT3. We propose a model in which SOCS2 acts as a negative regulator of TLR-induced DC activation. The delayed expression of SOCS2 provides a mechanism of late-phase counterregulation and limitation of inflammation-driving DC activity.
authors.affiliation: Division of Allergy and Immunology, Department of Molecular Biology, Paris Lodron University of Salzburg, 5020 Salzburg, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Posselt
authors.forename: Harald
authors.initials: H
authors.lastname: Schwarz
authors.forename: Albert
authors.initials: A
authors.lastname: Duschl
authors.forename: Jutta
authors.initials: J
authors.lastname: Horejs-Hoeck
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D005434:Flow Cytometry; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D051193:Toll-Like Receptors