Dectin-1 Stimulation Induces Suppressor of Cytokine Signaling 1, Thereby Modulating TLR Signaling and T Cell Responses

Abstract

Suppressor of cytokine signaling (SOCS) proteins serve as negative regulators of cytokine receptor signaling. However, SOCS proteins are not only induced via the JAK/STAT pathway, but are also transcribed on triggering of pattern recognition receptors such as TLRs. We now show that SOCS1 can also be induced by the non-TLR pattern recognition receptor Dectin-1 in murine bone marrow-derived dendritic cells and macrophages (BMMs). The C-type lectin Dectin-1 binds to yeasts and signals either in an autonomous manner or can be triggered in combination with TLRs. In our study, SOCS1 was expressed independently of any TLR engagement as a direct target gene of the Dectin-1 ligand Zymosan. Induction of SOCS1 was mediated by a novel pathway encompassing the tyrosine kinases Src and Syk that activated the downstream kinase proline-rich tyrosine kinase 2. Proline-rich tyrosine kinase 2, in turn, caused activation of the MAPK ERK, thereby triggering SOCS1 induction. SOCS1 did not modulate Dectin-1 signaling but affected TLR signaling, leading to decreased and abbreviated NF-κB activation in BMMs triggered by TLR9. Furthermore, IL-12 and IL-10 secretion were inhibited by SOCS1. We additionally observed that IL-17–producing Th cells were clearly increased by SOCS1 in BMMs. Our results show that SOCS1 is expressed via a new, NF-κB–independent pathway in Dectin-1–triggered murine BMMs and influences TLR cross talk and T cell priming.

Dectin-1-mediated Signaling Leads to Characteristic Gene Expressions and Cytokine Secretion via Spleen Tyrosine Kinase (Syk) in Rat Mast Cells

“…The list of the significantly up-regulated genes in RBL-2H3 cells overexpressing Dectin-1 WT after 2 h of curdlan stimulation is shown in Table 1. Consistent with previous studies in macrophages and DCs, gene expressions of TNF-␣ (12, 13, 15), IL-4/IL-13 (38,39), early growth response transcription factor 3 (40,41), and suppressor of cytokine signaling 1 (42) were also up-regulated in curdlan-stimulated mast cells. Interestingly, curdlan did not stimulate gene expressions that were previously reported in macrophages and DCs, such as IL-1␤ (43, 44), IL-2 (18), [18][19][20], and IL-12 (18,20).…”

“…With immunoblotting using IB␣, IB kinase, and phospho-IB kinase antibodies, NF-B is not activated with curdlan stimulation in RBL-2H3 cells (data not shown). Goodridge et al (63) demonstrated that although Dectin-1 signals directly activate NF-B in mouse DCs, Dectin-1 signaling alone does not activate NF-B in mouse macrophages (14,42,63). According to this, Dectin-1-mediated activation of NF-B in mast cells may not activate in the same manner as that in macrophages.…”

The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

“…Activation of dectin-1 by C. albicans has been shown to induce interleukin 10 (IL-10), which has an inhibitory effect over TLR by targeting MyD88 (10,11). Similar studies have also shown that dampening of TLR-triggered protective immune responses is mediated by dectin-1-induced expression of suppressor of cytokine signaling 1 (SOCS-1) (12).…”

Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist

“…It has recently been reported that the soluble form of β-glucan does not activate Dectin-1 signaling (28). Additionally, Dectin-1 signaling inhibits TLR9-mediated cytokine production through suppressor of cytokine signaling 1 induction (29). Therefore, we examined the agonistic activity of SPG.…”