Suppressor of Cytokine Signaling 1 Inhibits IL-10-Mediated Immune Responses

Abstract

IL-10 has proved to be a key cytokine in regulating inflammatory responses by controlling the production and function of various other cytokines. The suppressor of cytokine signaling (SOCS) gene products are a family of cytoplasmic molecules that are essential mediators for negatively regulating cytokine signaling. It has been previously shown that IL-10 induced SOCS3 expression and that forced constitutive expression of SOCS3 inhibits IL-10/STAT3 activation and LPS-induced macrophage activation. In this report, we show that, in addition to SOCS3 expression, IL-10 induces SOCS1 up-regulation in all cell lines tested, including Ba/F3 pro-B cells, MC/9 mast cells, M1 leukemia cells, U3A human fibroblasts, and primary mouse CD4+ T cells. Induction of SOCS molecules is dependent on STAT3 activation by IL-10R1. Cell lines constitutively overexpressing SOCS proteins demonstrated that SOCS1 and SOCS3, but not SOCS2, are able to partially inhibit IL-10-mediated STAT3 activation and proliferative responses. Pretreatment of M1 cells with IFN-γ resulted in SOCS1 induction and a reduction of IL-10-mediated STAT3 activation and cell growth inhibition. IL-10-induced SOCS is associated with the inhibition of IFN-γ signaling in various cell types, and this inhibition is independent of C-terminal serine residues of the IL-10R, previously shown to be required for other anti-inflammatory responses. Thus, the present results show that both SOCS1 and SOCS3 are induced by IL-10 and may be important inhibitors of both IL-10 and IFN-γ signaling. IL-10-induced SOCS1 may directly inhibit IL-10 IFN-γ signaling, while inhibition of other proinflammatory cytokine responses may use additional IL-10R1-mediated mechanisms.

Reprogramming of IL-10 Activity and Signaling by IFN-γ

“…In contrast, in our experiments, Stat3 function was suppressed, possibly secondary to heterodimerization with high levels of activated Stat1, but levels of Stat3 tyrosine phosphorylation were preserved. The intact activation of Jak1 and Stat3 by IL-10 in IFN-␥-activated macrophages is consistent with previous reports showing that IL-10 signaling can be relatively resistant to inhibition by SOCS proteins in a cell type-dependent manner (37,38). Our results showing that IFN-␥ regulates the balance of Stat1 and Stat3 activation by IL-10, together with the results from Biron and O'Shea and colleagues (36) demonstrating differential activation of Stat1 and Stat4 by IFN-␣␤ over the time course of a viral infection in vivo, support the notion that dynamic regulation of the activation of different STATs by cytokines plays an important role in determining the activity of pleiotropic cytokines.…”

Dendritic Cells Transduced with SOCS1 Gene Exhibit Regulatory DC Properties and Prolong Allograft Survival

“…Reports indicate that overexpression of the SOCS-3 gene promotes IL-10 production, and that IL-10 can induce SOCS1 and SOCS-3 expressions. We also observed that overexpression of SOCS1 can promote IL-10 expression of DCs (32,33). These findings attracted speculation that IL-10 very likely plays a pivotal role in the differentiation process of regulatory DCs.…”

Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation

“…Previous studies report discovered that IL-10 rapidly induces SOCS3 in a STAT3-dependent manner [40,41] . Because SOSC3 can negatively regulate responses to different activating cytokines and bacterial products, it is speculated that the anti-inflammatory action of IL-10 is due to induction of SOCS3 [42] .…”