Suppressor of Cytokine Signaling (SOCS) Proteins Indirectly Regulate Toll-like Receptor Signaling in Innate Immune Cells

Abstract

Suppressor of cytokine signaling (SOCS) proteins constitute a class of negative regulators for Janus kinase/ signal transducer and activator of transcription (JAK/ STAT) signaling pathways. These intracellular proteins are induced by cytokine signaling, but they can also be induced by stimulation of Toll-like receptors (TLR). It has even been suggested that SOCS proteins are important negative regulators of TLR signaling. Here we have elucidated the nature of the regulatory role of SOCS in TLR signaling. Induction of SOCS-3 and cytokine-inducible Src homology 2-containing protein (CIS) by TLR stimulation was strictly dependent on MyD88 but showed differing needs in case of SOCS-1. However, induction of SOCS proteins by TLR ligands was independent of type I interferon. In macrophages overexpressing SOCS, we were not able to observe an inhibitory effect of SOCS-1, SOCS-2, SOCS-3, or CIS on prototypical TLR target genes such as tumor necrosis factor-␣. However, we found that TLR-2, TLR-3, TLR-4, and TLR-9 stimulation induced interferon-␤ (IFN-␤), which is able to exert auto-and paracrine signaling, leading to the activation of secondary genes like IP-10. SOCS-1 and, to a lesser extent, SOCS-3 and CIS were able to inhibit this indirect signaling pathway following TLR stimulation, whereas neither MAP kinase nor NFB signaling were affected. However, STAT-1 tyrosine phosphorylation following TLR triggering was severely impaired by SOCS-1 overexpression. Thus, our data suggest that SOCS proteins induced by TLR stimulation limit the extent of TLR signaling by inhibiting type I IFN signaling but not the main NFB pathway.

Suppressor of cytokine signaling-1 selectively inhibits LPS-induced IL-6 production by regulating JAK–STAT

“…1D, that I B induction by LPS showed no difference between Raw͞SOCS-1 and Raw͞Neo. This result is consistent with a study that showed that SOCS-1 does not affect the NF-B pathway in LPS signaling (19). Taken together, these findings suggest that SOCS-1 selectively inhibits IL-6 production and does not affect I B induction through the MyD88-dependent pathway in LPS signaling.…”

Interleukin-10 inhibits tumor necrosis factor-α production in lipopolysaccharide-stimulated RAW 264.7 cells through reduced MyD88 expression

“…SOCS3 seems to attenuate pro-inflammatory aspects of TLR signaling directly. [19][20][21][22] However, the present study suggests that IL-10 may exhibit the anti-inflammatory action via reduced MyD88 expression. In fact, MyD88 deficiency is known to lead to diminished inflammatory cytokine production.…”

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

“…SOCS1 also binds to tyrosine-phosphorylated Mal through its interaction with Bruton's tyrosine kinase, leading to the suppression of Mal-dependent p65 phosphorylation and transactivation of NF-kB (48). Another important mechanism of the suppression of APC activation by SOCS1 is inhibition of the secondary activated JAK-STAT pathway (49,50). The Toll/IL-1R domain-containing adaptor protein-inducing IFN-b-IFN-regulatory factor 3 pathway rapidly induces IFN-b, which in turn activates JAK-STAT1 and contributes to the expression of IFN- inducible genes (51).…”