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.

Genome-wide transcriptome analysis of dendritic cells in a model of acute and persistent infection

“…al also demonstrated that the silencing of SOCS2 results in enhanced cytokine production, especially in case of IL-10 and IL-1β [73]. Our results corroborate these findings as we detected enhanced relative gene expression of IL-10 after PGN stimulation ( Figure 10G).…”

“…Moreover, in T+PGN samples we detected a more robust gene expression down regulation than in N+PGN samples. It is important to note here that Posselt and his colleagues demonstrated that in primary human monocytederived DCs, SOCS2 shows a time-delayed expression pattern after LPS stimulation [73].…”

SOCS2 (suppressor of cytokine signaling 2)

“…Upon induced inflammatory challenge, absence of SOCS2 has been shown to render multiple immune cell types incapable of mounting anti-inflammatory responses. Under resting conditions, SOCS2 null animals also display a population-bias towards a proinflammatory phenotype (Machado et al, 2006;Lee et al, 2010;Knosp et al, 2011;Posselt et al, 2011;Hu et al, 2012). SOCS2 is known to inhibit TGFβ, IL-4, IL-5, IL-10, IL-13 and IFNγ signaling (Knosp et al, 2011, Knosp et al, 2013.…”

“…SOCS2 also accelerates degradation of other members of the SOCS family such as SOCS1 and SOCS3 thus further impinging on downstream STAT signaling (Piessevaux et al, 2006;Tannahill et al, 2005). In turn, SOCS2 gene itself is under regulation of various inflammatory signals (e.g., LPS, dioxins, LipoxinA4) (Machado et al, 2006;Hu et al, 2009bHu et al, , 2012 and cytokines (e.g.,IL-4, IL-10, IFNβ, IFNγ) (Knosp et al, 2011;Posselt et al, 2011).…”

The state of receptor-dependent signal pathways in the agranulocytes from the peripheral blood of the reconvalescent patients following community-acquired pneumonia under the influence of microwave radiation

“…ограничивая провоспалительную активацию анти-генпрезентирующих клеток, а также натуральных киллеров (NK) [6][7][8][9]. Таким образом, состояние JAK/STAT-сигнального пути определяет эффективность про-цессов пролиферации, дифференцировки, роста, противовирусного ответа и т.д.…”