Suppressors of Cytokine Signaling Proteins Are Differentially Expressed in Th1 and Th2 Cells: Implications for Th Cell Lineage Commitment and Maintenance

Abstract

Positive regulatory factors induced by IL-12/STAT4 and IL-4/STAT6 signaling during T cell development contribute to polarized patterns of cytokine expression manifested by differentiated Th cells. These two critical and antagonistic signaling pathways are under negative feedback regulation by a multimember family of intracellular proteins called suppressor of cytokine signaling (SOCS). However, it is not known whether these negative regulatory factors also modulate Th1/Th2 lineage commitment and maintenance. We show here that CD4+ naive T cells constitutively express low levels of SOCS1, SOCS2, and SOCS3 mRNAs. These mRNAs and their proteins increase significantly in nonpolarized Th cells after activation by TCR signaling. We further show that differentiation into Th1 or Th2 phenotype is accompanied by preferential expression of distinct SOCS mRNA transcripts and proteins. SOCS1 expression is 5-fold higher in Th1 than in Th2 cells, whereas Th2 cells contain 23-fold higher levels of SOCS3. We also demonstrate that IL-12-induced STAT4 activation is inhibited in Th2 cells that express high levels of SOCS3 whereas IL-4/STAT6 signaling is constitutively activated in Th2 cells, but not Th1 cells, with high SOCS1 expression. These results suggest that mutually exclusive use of STAT4 and STAT6 signaling pathways by differentiated Th cells may derive in part, from SOCS3- or SOCS1-mediated repression of IL-12/STAT4- or IL-4/STAT6 signaling in Th2 and Th1 cells, respectively. Given the strong correlation between distinct patterns of SOCS expression and differentiation into the Th1 or Th2 phenotype, SOCS1 and SOCS3 proteins are therefore Th lineage markers that can serve as therapeutic targets for immune modulation therapy.

Cloning of common carp SOCS-3 gene and its expression during embryogenesis, GH-transgene and viral infection

“…Thus, we may suggest that these immune organs of carp are involved in cytokine (such as IL-12 and IFN-a/b) signalling induced by SVCV and require being regulated by SOCS-3, and then SOCS-3 acts as a negative-feedback loop to suppress these cytokine receptor signalling for balancing cytokine action. In addition, Wang et al found that trout SOCS-3 gene is higher expression induced by two cytokines in the monocyte/macrophage RTS-11 cell line than in fibroid RTG-2 cell line [18], and previous reports have also indicated that SOCS-3 is induced in T cells, B cells, neutrophils, macrophages and DCs by a variety of agents both in vitro and in vivo [3,7,42,43], which may explain why the induced expression of carp SOCS-3 gene was significantly up-regulated in the immune organs in this study. Noteworthily, in human, the inhibition of the IFN system by virus (HSV-1)-induced SOCS-3 can confer efficient viral replication, and SOCS-3 is up-regulated via activated STAT3 and it efficiently inhibits IFN-a/b signalling [38].…”

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

“…Members of the suppressor of cytokine signaling (SOCS) family of proteins are described as feedback inhibitors of a broad range of cytokine signaling pathways, regulating the amplitude and duration of the polarization influenced by T-bet or GATA-3 [17] . Notably, SOCS3 inhibits the signal transduction pathway implicating IFNγ [18] . D e t e r m i n i n g T h 1 / T h 2 b a l a n c e d u r i n g t h e radiotherapy protocol and, in particular, its long-term balance requires a longitudinal study.…”

Suppressors of Cytokine-Signaling Proteins Induce Insulin Resistance in the Retina and Promote Survival of Retinal Cells

“…Observation of cells by light microscopy after 24 h of hypoxia demonstrated that they were viable and healthy EAU induction. We induced EAU in C57BL/6 mice by active immunization with 150 g bovine interphotoreceptor retinoid binding protein (IRBP) and 300 g human IRBP peptide (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) in complete Freund's adjuvant containing the Mycobacterium tuberculosis strain H37RA (2.5 mg/ml) (13). Eyes for histology were harvested 0, 14, and 21 days postimmunization, fixed in 10% buffered formalin.…”

“…The eightmember SOCS family of proteins attenuates cytokine signals through interactions with cytokine/growth factor receptors and signaling proteins, leading to proteosomal degradation of the receptor complex (14 -16). SOCS pro-teins are rapidly induced in many cell types in response to cytokines (interferon [IFN]-␥, interleukin [IL]-1␤, and IL-6) or growth factors (ciliary neurotrophic factor, leukemia inhibitory factor, fibroblast growth factor, and insulin), and their effects are transient due to their short half-life (17)(18)(19). However, constitutive SOCS expression occurs in some tissues due to unabated stimulation by chronic inflammation or cellular stress, leading to silencing of critical cellular pathways and predisposition to organspecific disease development.…”