Putting out the fire: coordinated suppression of the innate and adaptive immune systems by SOCS1 and SOCS3 proteins

Abstract

The mounting of an effective immune response requires the coordinated function of both the innate and the adaptive arm of the immune system. Cells from both types of immunity respond to antigenic stimuli through a variety of surface and intracellular receptors and produce cytokines that tightly orchestrate the inflammatory response. The operation of feedback control mechanisms that regulate the duration and the amplitude of antigenic and cytokine receptor signaling is therefore required to prevent hyper-activation of the immune system that could lead to tissue destruction or autoimmunity. Suppressor of cytokine signaling (SOCS) proteins have been identified as a negative feedback loop to cytokine signaling. Recently, the generation of genetically engineered mouse models permitted the evaluation of their function in different processes of the immune responses. In this article, we review new insights into the modular structure of SOCS proteins and the function of SOCS1 and SOCS3 to negatively regulate activation and/or differentiation pathways in macrophages, dendritic cells, and T lymphocytes. Thus, SOCS family proteins are components of an emerging immunoregulatory mechanism that maintains the coordinated balance of both innate and adaptive immune responses.

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

“…MyD88 is a crucial common adaptor molecule that mediates both TLRs and IL-1 type 1 receptor activation (46,47), and MyD88 signaling in DCs is critical for the induction of EAM (16). SOCS1 negatively regulates the MyD88-dependent pathway by interacting with both IL-1R-associated kinase and NF-kB (17), which results in a decrease in the induction of inflammatory cytokines such as TNF-a and IL-6. In fact, production of these inflammatory cytokines was inhibited by the administration of SOCS1 DNA in the current study (Fig.…”

“…5A). SOCS1 protein has been shown to regulate T cell differentiation (17,18). To determine the differentiation of CD4 + T cells during EAM, we examined the heartinfiltrating CD4 + T cell populations by FACS analysis.…”

“…Recent lines of evidence indicate that SOCS proteins, originally identified as negative-feedback regulators in cytokine signaling, are involved in the regulation of TLR-mediated immune responses (17,18). The SOCS family is composed of eight members: cytokine-inducible Src homology 2 domain-containing protein and SOCS1 to SOCS7 (19,20).…”

Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine production

“…This increase in STAT5A/B-mediated transcription of several cytokine genes agrees with the model in which SOCS1 forms part of the negative feedback loop; decreased expression of the SOCS1 gene possibly leads to decreased protein levels in the cytoplasm. 52 This loss of SOCS1 protein would, therefore, allow STAT5A/B to translocate into the nucleus, where it binds and drives the expression of a large number of genes. 41 In addition, several of the cytokines we observed to be up-regulated, such as IL-6 and LIF, are reported to up-regulate the expression of SOCS1.…”

“…52 Immune responses implicated in signaling from SOCS family members have been linked to obesity and type-2 diabetes. 51 While decreased expression of other SOCS family members was observed, these genes did not reach our criteria for significance.…”